Modulation of the gut microbiome to treat mental disorders or diseases of the central nervous system

ABSTRACT

The present disclosure relates to methods of treating at least one symptom of a mental disorder or disease of the central nervous system in a subject by modulating the amount of GABA produced in the subject&#39;s gut. The present disclosure also relates to methods of culturing the bacterial strain new bacterial strains. Also disclosed are methods of identifying bacterial strains capable of producing GABA, and engineering strains to produce GABA.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 16/084,511 filed on Sep. 12, 2018, now U.S. Pat. No. 11,116,804, issued on Sep. 14, 2021, which is a National Application under 35 USC § 371 of International PCT Application PCT/US2017/022091, filed on Mar. 13, 2017, which claims priority to, and benefit of, U.S. Provisional Application No. 62/307,991, filed Mar. 14, 2016, the contents of each of which are herein incorporated by reference in their entireties.

GOVERNMENT FUNDING

This invention was made with government support under 3R01HG005824-02S1 awarded by the National Institute of Health. The government has certain rights in the invention.

INCORPORATION OF SEQUENCE LISTING

The contents of the text file named “HOBE-001-02US_SeqList.txt,” which was created on Aug. 6, 2021 and is 7.6 MB in size, are hereby incorporated by reference in their entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to compositions and methods for treating at least one symptom of a disease in a subject. In some cases, the disease is a mental disorder or a disease of the central nervous system. The present disclosure teaches treatment of the disease by modulating (e.g., increasing) the amount of endogenous GABA in a subject's body. In some embodiments, the present disclosure teaches modulating (e.g., increasing) the amount of GABA produced in the subject's gut by bacteria in the gut. For example, the present disclosure teaches administration to a subject in need thereof bacteria that are capable of producing GABA (e.g., inside a human gut).

The present disclosure also relates to methods of culturing previously uncultured bacterial strains. For instance, the present disclosure teaches the previously uncultured bacterial strain Evtepia gabavorous KLE1738. As set forth herein, newly uncultured bacterial strains such as Evtepia gabavorous KLE1738 can be cultured by providing growth factors necessary for the bacteria's growth and reproduction.

Also disclosed are methods of identifying bacterial strains capable of producing certain growth factors. For instance, described herein are methods of identifying bacterial strains capable of producing GABA, for instance under physiologically relevant conditions such as at a physiologically relevant pH.

BACKGROUND

The gut microbiome affects certain gastrointestinal and metabolic disorders, such as irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, celiac disease, obesity, heart disease, type I and II diabetes, and colon cancer.

Microbiological studies have so far been limited, by necessity, to cultivable microorganisms. By some estimates, in external environments, 99% of bacteria are thought to be uncultured. The development of new techniques for culturing previously uncultured or unculturable bacteria can thus help to expand the scope of microbiology research.

SUMMARY OF THE INVENTION

The present disclosure provides compositions and methods for treating diseases such as mental illness or diseases of the central nervous system. In some embodiments, the present disclosure teaches therapeutic compositions comprising one or more bacteria (e.g., purified bacteria) that are capable of producing GABA. The bacteria can be capable of producing GABA under physiologically relevant conditions, including within a human gut. The present disclosure also provides methods of treating a subject in need thereof comprising administering to a subject a therapeutic composition comprising GABA-producing bacteria. As set forth herein, the GABA-producing bacteria can produce GABA in the subject's gut. The GABA can diffuse into other systems of the subject's body (e.g., the circulatory and nervous systems). There, the endogenous GABA can act as a neurotransmitter. In some embodiments, increased levels of GABA (e.g., in the nervous system) can improve the symptoms of the mental illness or disease of the central nervous system.

In some embodiments, the present disclosure also provides methods for identifying bacteria that produce GABA in humans at a physiologically relevant pH range and uses for these bacteria to modulate GABA levels in humans to treat mental illness.

The present disclosure also relates to a method of culturing previously uncultivated bacterial species. For instance the present disclosure teaches the isolation and characterization of a bacterial species KLE1738, provisionally named Evtepia gabavorous. Growth of E. gabavorous requires the presence of the growth factor GABA, which can be supplied by GABA-producing bacteria such as Bacteroides fragilis KLE1758.

In one aspect, the present disclosure provides a therapeutic composition comprising at least one purified bacterial population consisting of bacteria capable of producing GABA in a subject in need thereof.

In some embodiments, the at least one bacterial population consists of a bacteria comprising a 16S rDNA sequence at least about 95% identical to a 16S rDNA sequence selected from one of Seq. ID. Nos. 1-31 set forth in Table 1. In some embodiments, the at least one purified bacterial population consists of bacteria selected from the group consisting of: Bacteroides caccae KLE1911; Bacteroides clarus KLE1930; Bacteroides dorei KLE1912; Bacteroides finegoldii KLE1931; Bacteroides fragilis KLE1958; Bacteroides massiliensis KLE1932; Bacteroides ovatus KLE1770; Bacteroides stercoris KLE1933; Bacteroides thetaiotaomicron KLE1934; Bacteroides uniformis KLE1913; Bacteroides vulgatus KLE1910; Bacteroides xylanisolvens KLE1935; Bifidobacterium adolescentis KLE 1879; Blautia obeum KLE1914; Blautia wexlerae KLE1916; Butyricimonas virosa KLE1938; Clostridium perfringens KLE1937; Clostridium sordellii KLE1939; Clostridium sp. KLE1862; Clostridium sp. KLE1918; Coprobacillus sp. KLE1779; Coprococcus sp. KLE1880; Dorea longicatena KLE1917; Eggerthella lenta KLE1926; Eubacterium rectale KLE1922; Gordonibacter pamelaeae KLE1915; Oscillibacter sp. KLE1928; Parabacteroides distasonis KLE2020; Parabacteroides merdae KLE1863; Ruminococcus gnavus KLE1940; Turicibacter sanguinis KLE1941, and combinations thereof.

In some embodiments, the at least one purified bacterial population consists of a bacteria comprising a 16S rDNA sequence at least about 95% identical to a 16S rDNA sequence selected from one of Seq. ID. Nos. 32-274 set forth in Table 2. In some embodiments, the at least one purified bacterial population consists of bacteria comprising a 16S rDNA sequence having at least 95% similarity to the 16S rDNA sequence selected from one of Seq. ID. Nos. 305-2217 set forth in Table 10. In some embodiments, the at least one purified bacterial population consists of bacteria comprising a DNA sequence which encodes an enzyme selected from: glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof. In some embodiments, the glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof, is encoded by a DNA sequence at least 70% similar in DNA sequence to any one of Seq. ID. Nos. 275-304 set forth in Table 3.

In some embodiments, the glutamate decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 4. In some embodiments, the putrescine aminotransferase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 5. In some embodiments, the gamma-aminobutyraldehyde dehydrogenase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 6. In some embodiments, the arginine decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 7. In some embodiments, the agmatinase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 8. In some embodiments, the omithine decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 9.

In some embodiments, the at least one purified bacterial population consists of bacteria comprising a 16S rDNA sequence having at least 95% similarity to a reference bacterium selected from the group consisting of: Escherichia coli MG1655; Escherichia coli Nissle 1917; or a combination thereof.

In some embodiments, the bacterial population consists of bacteria capable of producing GABA at a physiologically relevant pH. In some embodiments, the bacterial population consists of bacteria capable of producing GABA at a pH range between about 4.5 and about 7.5. In some embodiments, the bacterial population consists of bacteria capable of producing GABA inside the human gut.

In some embodiments, the composition is in the form of a probiotic, prebiotic, a capsule, a tablet, a caplet, a pill, a troche, a lozenge, a powders, a granule, a medical food, or a combination thereof. In some embodiments, the composition is administered as a fecal transplant.

In some embodiments, the bacteria are capable of producing GABA via expression of any combination of glutamate decarboxylase, putrescine aminotransferase, gamma-aminobutyraldehyde dehydrogenase, arginine decarboxylase, agmatinase, and/or ornithine decarboxylase.

In some embodiments, the therapeutic composition further comprises a purified bacterial strain that is cytotoxic or cytostatic to a GABA-consuming bacteria. In some embodiments, the GABA-consuming bacteria is Evtepia gabavorous or Firmicutes bacterium MGS:114.

In some embodiments, the therapeutic composition further comprises a prebiotic capable of stimulating the growth or GABA-production levels of a GABA-producing bacteria.

In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutic composition comprising at least one purified bacterial population consisting of bacteria capable of producing GABA in a subject in need thereof.

In one aspect, the present disclosure provides the use of a therapeutic composition comprising at least one purified bacterial population consisting of bacteria capable of producing GABA in the manufacture of a medicament for the treatment of a disease.

In one aspect, the present disclosure provides the use of a therapeutic composition comprising at least one purified bacterial population consisting of bacteria capable of producing GABA for the treatment of a disease.

In some embodiments, the disease or disorder is a mental disease or disorder. In some embodiments, the mental disease or disorder is selected from the group consisting of depression, bipolar disorder, schizophrenia, anxiety, anxiety disorders, addiction, social phobia, treatment-resistant major depressive disorder (TR-MDD), major depressive disorder and its subtypes (melancholic depression, atypical depression, catatonic depression, postpartum depression, and seasonal affective disorder), Neurodegenerative amyloid disorders (Parkinson's, Alzheimer's, and Huntington's diseases) orthostatic tremor, Lafora disease, restless leg syndrome, neuropathic pain, pain disorders, dementia, epilepsy, stiff-person syndrome, premenstrual dysphoric disorder, autism spectrum disorder, sleep disorders, and attention deficit hyperactivity disorder (ADHD), and combinations thereof. In some embodiments, treating a disease or disorder comprises decreasing at least one symptom of the disease or disorder, such as fatigue, insomnia, motor dysfunction, stress, persistent anxiety, persistent sadness, social withdrawal, substance withdrawal, irritability, thoughts of suicide, thoughts of self-harm, restlessness, low sex drive, lack of focus, seizures, memory loss, anger, bouts of emotional reactivity, confusion, pain, and muscle spasms, loss of appetite, altered intestine motility, and combinations thereof.

In some embodiments, the at least one bacterial population consists of a bacteria comprising a 16S rDNA sequence at least about 95% identical to a 16S rDNA sequence selected from one of Seq. ID. Nos. of 1-31 set forth in Table 1. In some embodiments, the at least one purified bacterial population consists of bacteria selected from the group consisting of: Bacteroides caccae KLE1911; Bacteroides clarus KLE1930; Bacteroides dorei KLE1912; Bacteroides finegoldii KLE1931; Bacteroides fragilis KLE1958; Bacteroides massiliensis KLE1932; Bacteroides ovatus KLE1770; Bacteroides stercoris KLE1933; Bacteroides thetaiotaomicron KLE1934; Bacteroides uniformis KLE1913; Bacteroides vulgatus KLE1910; Bacteroides xylanisolvens KLE1935; Bifidobacterium adolescentis KLE 1879; Blautia obeum KLE1914; Blautia wexlerae KLE1916; Butyricimonas virosa KLE1938; Clostridium perfringens KLE1937; Clostridium sordellii KLE1939; Clostridium sp. KLE1862; Clostridium sp. KLE1918; Coprobacillus sp. KLE1779; Coprococcus sp. KLE1880; Dorea longicatena KLE1917; Eggerthella lenta KLE1926; Eubacterium rectale KLE1922; Gordonibacter pamelaeae KLE1915; Oscillibacter sp. KLE1928; Parabacteroides distasonis KLE2020; Parabacteroides merdae KLE1863; Ruminococcus gnavus KLE1940; Turicibacter sanguinis KLE1941, and combinations thereof.

In some embodiments, the at least one purified bacterial population consists of a bacteria comprising a 16S rDNA sequence at least about 95% identical to a 16S rDNA sequence selected from one of Seq. ID. Nos. of 32-274 set forth in Table 2.

In some embodiments, the at least one bacterial population consists of a bacteria comprising a 16S rDNA sequence at least about 95% identical to any one of Seq ID Nos. 305-2217 set forth in Table 10.

In some embodiments, the at least one purified bacterial population consists of bacteria comprising a DNA sequence which encodes an enzyme selected from: glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof.

In some embodiments, the glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof, is encoded by a DNA sequence at least 70% similar to a DNA sequence selected from one of Seq. ID. Nos. 275-304 set forth in Table 3.

In some embodiments, the glutamate decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 4. In some embodiments, the putrescine aminotransferase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 5. In some embodiments, the gamma-aminobutyraldehyde dehydrogenase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 6. In some embodiments, the arginine decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 7. In some embodiments, the agmatinase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 8. In some embodiments, the omithine decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 9.

In some embodiments, the bacteria is genetically engineered to produce GABA. In some embodiments, the bacteria is engineered to produce GABA via expression of glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof.

In some embodiments, wherein the glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof, is encoded by a DNA sequence at least 70% similar in DNA sequence selected from one of Seq. ID. Nos. of 275-304 set forth in Table 3.

In some embodiments, the glutamate decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 4. In some embodiments, the putrescine aminotransferase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 5. In some embodiments, the gamma-aminobutyraldehyde dehydrogenase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 6. In some embodiments, the arginine decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 7. In some embodiments, the agmatinase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 8. In some embodiments, the ornithine decarboxylase is encoded by a DNA sequence at least 95% similar in DNA sequence to a gene with a EMBL/GENBANK/DDBJ ID found in Table 9.

In some embodiments, the at least one purified bacterial population consists of bacteria comprising a 16S rDNA sequence having at least 95% similarity to a reference bacterium selected from the group consisting of: Escherichia coli MG1655; Escherichia coli Nissle 1917; or a combination thereof.

In some embodiments, the bacterial population consists of bacteria capable of producing GABA at a physiologically relevant pH. In some embodiments, the bacterial population consists of bacteria capable of producing GABA at a pH range between about 4.5 and about 7.5. In some embodiments, bacterial population consists of bacteria capable of producing GABA inside the human gut. In some embodiments, the composition is administered as a fecal transplant. In some embodiments, the composition is administered as a probiotic. In some embodiments, the bacteria are capable of producing GABA via expression any combination of glutamate decarboxylase, putrescine aminotransferase, gamma-aminobutyraldehyde dehydrogenase, arginine decarboxylase, agmatinase, ornithine decarboxylase, and combinations thereof.

In some embodiments, the at least one bacterial strain is cytotoxic or cytostatic to a GABA-consuming bacteria. In some embodiments, the GABA-consuming bacteria is Evtepia gabavorous or Firmicutes bacterium MGS:114.

In some embodiments, the method of treating a subject further comprises identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of GABA in the subject's stool. In some embodiments, the initial amount of GABA in the subject's stool is below about 8 μg per gram of wet or dry stool. In some embodiments, the amount of GABA in the subject's stool is increased relative to the initial amount after administering the therapeutic composition.

In some embodiments, the method of treating a subject further comprises identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of GABA-producing bacteria in the subject's stool. In some embodiments, the initial amount of GABA-producing bacteria in the subject's stool is less than about 10% of total bacteria as measured by 16S sequence mapping. In some embodiments, at least one GABA-producing bacteria is increased in the subject's stool relative to the initial amount of GABA-producing bacteria in the subject's stool after administering the therapeutic composition.

In some embodiments, the method of treating a subject further comprises identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of GABA in the subject's blood or serum. In some embodiments, the amount of GABA in the subject's blood or serum is below about 10 μg per liter of blood. In some embodiments, the amount of GABA in the subject's blood or serum is increased relative to the initial amount after administering the therapeutic composition.

In some embodiments, the method of treating a subject further comprises identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an amount of GABA in the subject's brain. In some embodiments, the amount of GABA in the subject's brain is below about 1.0 mM/kg. In some embodiments, the amount of GABA in the subject's brain is increased relative to the initial amount after administering the therapeutic composition.

In some embodiments, the method of treating a subject further comprises identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of expression of GABA-producing enzymes in the subject's stool. In some embodiments, the GABA-producing enzymes are selected from glutamate decarboxylase, putrescine aminotransferase, gamma-aminobutyraldehyde dehydrogenase, arginine decarboxylase, agmatinase, ornithine decarboxylase, and combinations thereof. In some embodiments, the initial amount of enzyme expression is measured by qPCR. In some embodiments, the expression of enzymes is increased relative to the initial amount of enzyme expression after administering the therapeutic composition.

In some embodiments, the method of treating a subject further comprises identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of GABAergic response in the subject's brain. In some embodiments, the amount of the GABAergic response in the subject's brain is increased relative to the initial amount after administering the therapeutic composition. In some embodiments, the therapeutic composition comprises a prebiotic capable of stimulating the growth or GABA production of GABA-producing bacteria.

In one aspect, the present disclosure provides a method of culturing a GABA-dependent bacteria, comprising disposing at least one live GABA-dependent bacterial cell on a suitable substrate, and providing a source of GABA.

In some embodiments, the suitable substrate is agar. In some embodiments, providing a source of GABA comprises co-culturing with another bacterial strain, said strain is capable of producing GABA. In some embodiments, GABA is added to the substrate. In some embodiments, the GABA-dependent bacteria is E. gabavorous.

In one aspect, the present disclosure provides a method of identifying a bacterial strain or strains capable of producing GABA at a physiologically relevant pH of the human intestinal tract, comprising:

(a) dispersing a sample believed to contain GABA-producing bacteria within a substrate, the substrate being at least partially permeable to GABA, (b) contacting the substrate loaded with potential GABA-producing bacteria with a GABA-dependent bacterium; and (c) identifying a GABA-producing bacteria by observing the formation of a colonies of the GABA-dependent bacteria around potential GABA-producing bacteria in the substrate.

In some embodiments, the substrate is being buffered to maintain the pH at a physiologically range found in the human gastrointestinal tract. In some embodiments, the GABA-dependent bacteria is Egabavorous. In some embodiments, the pH range is between about 4.5 and about 7.5.

The present disclosure provides compositions and methods for treating mental illness or disease of the central nervous system in a subject and therapeutic compositions for the same. The method can comprise administering to the subject a bacterium and/or multiple bacteria capable of producing endogenous GABA in the subject's gut at a physiologically relevant pH. The present technology can have the advantage of alleviating the symptoms of a mental illness or disease of the central nervous system without the aid of synthetic medications (e.g., antidepressants), which can have unwanted side-effects, or in combination with existing medications. Additionally, the present technology can have the advantage of further improving the digestive health of the subject, such as improving intestinal motility and reducing gastrointestinal pain. Additional features and advantages of the present technology will be apparent to one of skill in the art upon reading the Detailed Description of the Invention, below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a pair of images (left and top right) that show a co-culture assay to grow and identify previously unculturable bacteria. The inset at the top right shows a close-up of the indicated region of the image at the left.

FIG. 1B shows the growth of Evtepia gabavorous KLE1738 in the presence of the helper bacteria Bacteroides fragilis KLE1758.

FIG. 2A shows the growth of Evtepia gabavorous KLE1738 in the presence of the supernatant from Bacteroides fragilis.

FIG. 2B shows a lack of growth of Evtepia gabavorous KLE1738 in the presence of the empty vehicle.

FIG. 2C shows the growth of Evtepia gabavorous in the presence of the most polar fraction of the supernatant from Bacteroides fragilis KLE1758.

FIG. 2D shows a close-view of the lack of growth of Evtepia gabavorous KLE1738 in the presence of the empty vehicle.

FIG. 2E shows a close-view of the growth of Evtepia gabavorous KLE1738 in the presence of the supernatant from Bacteroides fragilis KLE1758.

FIG. 2F shows a close-view of the lack of growth of Evtepia gabavorous KLE1738 in the presence of the empty vehicle (bacterial media).

FIG. 2G shows a table of potential growth factors for E. gabavorous KLE1738, with green indicating induction of growth.

FIG. 3 shows a proposed GABA metabolism of E. gabavorous KLE1738.

FIG. 4A shows GABA production of B. fragilis KLE1758 is observed only at a pH of 5.5 and below, highlighting the importance of acidic pH on GABA production for certain strains or species of bacteria.

FIG. 4B shows an assay for the identification of GABA-producing bacteria, capable of producing GABA at a pH between 4.5 and 7.5, using the GABA-requirement of E. gabavorous KLE1738. The medium was heavily buffered to maintain a pH of the desired range and identify strains of bacteria capable of producing GABA at a pH physiologically relevant to the human gut.

FIG. 4C shows a phylogenetic tree of GABA producers, capable of producing GABA at a pH of about 4.5 to about 7.5, identified by the methods herein.

FIG. 5 shows GABA production capabilities of several strains identified using the screen described in Example 7. The ability of organisms to produce GABA at a range of pH conditions is highlighted.

FIG. 6A shows the growth of E. gabavorous KLE1738 in the presence of E. coli that has been engineered to express glutamate decarboxylase gadA.

FIG. 6B shows the growth of E. gabavorous KLE1738 in the presence of E. coli that has been engineered to express glutamate decarboxylase gadB.

FIG. 6C shows the growth of E. gabavorous KLE1738 in the presence of B. fragilis KLE 1758 that is known to produce GABA.

FIG. 6D shows the absence of growth of E. gabavorous KLE1738 in the presence of E. coli that has been engineered to express glutamate decarboxylase gadC.

FIG. 6E shows the absence of growth of E. gabavorous KLE1738 in the presence empty vector.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to compositions and methods for treating or decreasing a symptom of a disease in a subject. The disease can be a mental illness or a disease of the central nervous system. After identifying a subject with a mental illness or disease of the central nervous system, the method can comprise determining whether the subject would benefit from an increase in endogenous GABA, for instance by measuring the amount of GABA in the subject's stool, blood serum, or other bodily fluids, measuring levels of GABA in different regions of the brain, measuring the GABAergic response in different regions in the brain, measuring activity of GABA producing enzymes in stool, or by measuring the amount of GABA-producing bacteria in the subject's stool. The method can further comprise administering to the subject a GABA-producing bacterium or bacteria that can be capable of producing GABA in the subject's gut, (e.g., at a physiologically relevant pH of the gut).

Some bacteria produce GABA from gamma-aminobutyrate to maintain intracellular pH homoeostasis in order to overcome acid stress. As set forth herein, the production of GABA by microbes (e.g., bacteria) in the human gut can impact the health of a subject. For instance, GABA produced by bacteria in the human gut can act as a neurotransmitter to treat a mental illness, a disease of the central nervous system, or improve gastrointestinal health in a subject.

Definitions

As used herein “administer” and “administration” encompasses embodiments in which one person directs another to consume a bacteria or a bacterial composition in a certain manner and/or for a certain purpose, and also situations in which a user uses bacteria or a bacterial composition in a certain manner and/or for a certain purpose independently of or in variance to any instructions received from a second person. Non-limiting examples of embodiments in which one person directs another to consume a bacteria or bacterial composition in a certain manner and/or for a certain purpose include when a physician prescribes a course of conduct and/or treatment to a patient, when a parent commands a minor user (such as a child) to consume bacteria or a bacterial composition, when a trainer advises a user (such as an athlete) to follow a particular course of conduct and/or treatment, and when a manufacturer, distributer, or marketer recommends conditions of use to an end user, for example through advertisements or labeling on packaging or on other materials provided in association with the sale or marketing of a product.

The term “isolated” encompasses a bacterium or other entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature, such as human stool, or in an experimental setting, such as a Petri plate consisting of artificial growth medium), and/or (2) produced, prepared, purified, and/or manufactured by the hand of man. Isolated bacteria may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated bacteria are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components (such as other bacterial species). The terms “purify,” “purifying” and “purified” refer to a bacterium or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production, as recognized by those skilled in the art of bacterial cultivation. A bacterium or a bacterial population may be considered purified if it is isolated at or after production, such as from a material or environment containing the bacterium or bacterial population, and a purified bacterium or bacterial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered “isolated.” In some embodiments, purified bacteria and bacterial populations are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. In the instance of bacterial compositions provided herein, the one or more bacterial types present in the composition can be independently purified from one or more other bacteria produced and/or present in the material or environment containing the bacterial type. Bacterial compositions and the bacterial components thereof are generally purified from residual habitat products.

As used herein, “probiotic” is understood to mean “Live microorganisms which when administered in adequate amounts confer a health benefit on the host”, as currently defined by the World Health Organization.

As used herein, “prebiotic” is understood to mean an ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota that may (or may not) confer benefits upon the host.

As used herein, “medical food” is understood to mean “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation”, as defined by 5(b) of the Orphan Drug Act (21 U.S.C. 360ee (b) (3)).

As used herein “initial amount” is understood to mean the amount of a substance, e.g., GABA in an aliquot of sample prior to administration of GABA-producing bacteria to the subject. Initial amount can be measured in terms of concentration. For instance, an initial amount can be measured in terms of micrograms of substance per milliliter of sample, e.g., micrograms of GABA per milliliter of blood or serum (μg GABA/mL blood or serum). The initial amount of can also be measured, for instance, as the amount of GABA in regions of the brain, such as the prefrontal cortex prior to administration of the GABA-producing bacteria. The amount of GABA can be represented in terms of millimoles of GABA per kg tissue (mmol GABA per kg of brain tissue). The initial amount can also be measured, for instance, as the amount of GABA in a subject's stool sample prior to administration of GABA-producing bacteria to the subject. The amount of GABA can be represented in terms of micrograms of GABA per gram of stool (μg GABA/g stool). The initial amount can also be the level of expression of GABA producing enzymes in the stool (log change of reads), as measured by qPCR or other appropriate method. Unless otherwise defined herein, stool is weighed when wet or dry, i.e., without active drying, and within one hour of production of the stool. For instance, the stool can be weighed within 45 minutes, 30 minutes, 15 minutes, 10 minutes, or within 5 minutes of production of the stool.

As used herein, a “GABAergic response” means the response of a given organ (e.g., the brain or vagus nerve) to differences in the concentrations of GABA, GABA producing bacteria, or prebiotics to which it is exposed. A GABAergic response can include a change in concentrations of GABA as well as expression levels and/or activity of different GABAA, GABAB, and/or GABAc receptors.

“GABA-producing bacteria” is understood to mean bacteria that can produce measurable quantities of GABA, as detected by LC/MS, ELISA, or other appropriate analytical assays. In some embodiments, GABA-producing bacteria can produce GABA under the physiological conditions in a human, e.g., under the pH, and temperature of the human gut.

“Physiologically relevant pH” of the human intestinal tract is understood to mean a pH range that exists in the body. For instance, a pH range that is physiologically relevant to the human gut can be in the range of about 4.5 to about 7.5.

The term “gut” is understood to refer to the human gastrointestinal tract, also known as the alimentary canal. The gut includes the mouth, pharynx, oesophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestines (cecum and colon) and rectum.

As used herein, “bacteria” or “bacterial strain” is understood to mean a species of bacteria. A “bacterium” is understood as a single bacterial cell of a given species.

The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

The term “EMBL/GenBank/DDBJ ID” refers to an accession number, which when used as in input for databases such as the European Molecular Biology Laboratory (EMBL), GenBank, or DNA Data Bank of Japan (DDBJ), via their respective internet websites, enables access to information, such as nucleotide sequence of a gene, and the bacterium encoding that sequence in its genome. The EMBL/GenBank/DDBJ ID is used in this application as a convenient means to access sequence information.

Gamma-Aminobutyric Acid (GABA)

The term “GABA” is understood to mean gamma-aminobutyric acid (γ-aminobutyric acid). GABA has the chemical structure:

GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. It plays a principal role in reducing neuronal excitability throughout the nervous system. GABA can be a difficult compound to deliver therapeutically due to efflux and half-life limitations. For example, in rodents, the brain efflux rate of GABA was found to be 17 times higher than the influx rate. Additionally, GABA only has a half-life of only 17 minutes in mice. Accordingly, because of the short half-life of GABA in vivo, oral GABA supplementation can be ineffective, as it may require frequent dosing, even with slow release capsules.

The present disclosure provides for delivering a therapeutic composition of one or more bacteria that can produce GABA within the intestinal tract, in order to consistently deliver GABA into systemic circulation (e.g., into the nervous system). The endogenously produced GABA can also activate vagal nerve receptors directly. This can mitigate the inherent half-life of GABA.

In some embodiments, the microbiome can influence GABA levels and the GABAergic response in the brain. For instance, germ-free animals can have substantially reduced luminal and serum levels of GABA. Without wishing to be bound by theory, this suggests the microbiome is important in regulating levels of this important neurotransmitter. As set forth herein, GABAergic modulation by microbiome intervention (e.g., using methods and compositions described herein) can have therapeutic potential.

In some embodiments, GABA can play a role in mental illness or disease of the central nervous system. For instance, in some embodiments, low levels of GABA can be associated with depression, bipolar disorder, schizophrenia, anxiety, anxiety disorders, addiction, social phobia, treatment-resistant major depressive disorder (TR-MDD), major depressive disorder and its subtypes (melancholic depression, atypical depression, catatonic depression, postpartum depression, and seasonal affective disorder), Neurodegenerative amyloid disorders (Parkinson's, Alzheimer's, and Huntington's diseases) orthostatic tremor, Lafora disease, restless leg syndrome, neuropathic pain, pain disorders, dementia, epilepsy, stiff-person syndrome, premenstrual dysphoric disorder, autism spectrum disorder, sleep disorders, and attention deficit hyperactivity disorder (ADHD). As set forth herein, the present disclosure provides increasing the amount of endogenous GABA in a subject can decrease levels of mental illness or disease of the central nervous system in the subject.

In some embodiments, GABA produced by gut bacteria can play a role in mental illness or disease of the central nervous system via the vagus nerve, connecting the intestinal tract to the peripheral and central nervous systems.

In some embodiments, GABA produced by gut bacteria can play a role in mental illness or disease of the central nervous system via affecting circulating levels of systemic GABA in the host, which can influence the peripheral and central nervous systems.

Means of GABA Production by Microbes

Bacteria can produce GABA using a variety of different pathways. Set forth below are exemplary pathways that bacteria and other microbes can use to produce GABA (e.g., in vivo). As set forth below, any of the GABA production pathways described herein can be naturally occurring in a given bacterium. Alternatively, a necessary enzyme or grouping of enzymes can be added to the DNA sequence of a bacteria to enable the bacteria to produce GABA.

Glutamate Pathway

In some embodiments, microbes can produce GABA using the glutamate decarboxylase enzyme (e.g., glutamate decarboxylase EC 4.1.1.15). In some embodiments, glutamate decarboxylase is capable of directly converting glutamate to GABA.

Putrescine to 4-Aminobutanal Pathway

In some embodiments, microbes can produce GABA using the putrescine to 4-aminobutanal pathway. The microbes can then convert 4-aminobutanal to GABA. In some embodiments, putrescine aminotransferase (for instance, putrescine aminotransferase EC 2.6.1.82) can be used to convert putrescine to 4-aminobutanal. The 4-aminobutanal can then be converted in the presence of gamma-aminobutyraldehyde dehydrogenase (e.g., gamma-aminobutyraldehyde dehydrogenase (EC 1.2.1.19)) to GABA.

Arginine to Agmatine to Putrescine Pathway

In some embodiments, microbes can produce GABA using the arginine to agmatine to putrescine Pathway. Once the putrescine is produced, it can be converted as described above (e.g., using the putrescine to 4-aminobutanal pathway) to GABA. In some embodiments, arginine decarboxylase (e.g., arginine decarboxylase (EC 4.1.1.19)) can convert arginine to agmatine. Agmatine can then be converted to putrescine using agmatinase (e.g., agmatinase (EC 3.5.3.11)).

L-Omithine to Putrescine Pathway

In some embodiments, ornithine decarboxylase (e.g., ornithine decarboxylase (EC 4.1.1.17)) can be used to convert ornithine to putrescine. Once the putrescine is produced, it can be converted as described above (e.g., using the putrescine to 4-aminobutanal pathway) to GABA.

Bacterial Strains

The present disclosure provides bacterial strains (e.g., purified strains) and therapeutic compositions comprising the same for administration to a subject in need thereof. The bacteria can be naturally occurring, or can be engineered (e.g., through strain engineering or selection) to produce GABA. In some embodiments, one strain of GABA-producing bacteria can be administered to a subject. In some embodiments, multiple strains of GABA-producing bacteria can be administered to a subject in need thereof. In some embodiments, the one or more bacteria (e.g., purified bacteria) can act synergistically. For instance, the multiple bacteria can act synergistically to produce high levels of GABA. In some embodiments, the one or more bacteria can also help to reduce the number of GABA-consuming bacteria in a human gut. Accordingly, any one, or any combination of the GABA-producing bacteria taught herein can be administered to a subject in need thereof.

In some embodiments, the bacteria taught herein can produce GABA at physiologically relevant conditions, such as under the conditions of the human gut. In some embodiments, the GABA-producing bacteria taught herein can produce GABA a pH relevant to the human gut is between about 4.5 and about 7.5. For instance, the pH can be about 4.5, 5.0, 5.5, 6.0, 6.5, 7.0 7.5, or any value between about 4.5 and 7.5.

The ability to produce GABA at physiologically relevant pH is important in view of the pH restrictions of GABA production in many bacteria. For example, E. coli is unable to produce GABA above a pH of 4.5. Instead, without wishing to be bound by theory, it can use conversion of glutamate to GABA coupled with GABA export, for example, as a means to neutralize the intracellular environment. Accordingly the present disclosure bacteria capable of producing GABA at a pH relevant to the host environment, such as the more neutral large intestines (e.g., between about pH 4.5 and about pH 7.5). In some embodiments, the bacteria taught herein can also produce GABA under other relevant conditions that exist within the human gut. That is, the GABA-producing bacteria taught herein can produce GABA in the absence of oxygen, in a nutrient-competitive and fluctuating environment, and in the absence of light.

Natural Strains

In some embodiments, the GABA-producing bacteria can be identified by having a 16S nucleic acid sequence substantially similar to the 16S sequences of reference bacteria listed in Table 1, with a Seq. ID. No. of 1-31. In some embodiments, the GABA-producing bacteria can have at least 90% 16S sequence similarity to the 16S sequences given in Table 1 (e.g., at least 91% similarity, at least 92% similarity, at least 93% similarity, at least 94% similarity, at least 95% similarity, at least 96% similarity, at least 97% similarity, at least 98% similarity, at least 99% similarity, at least 99.5% similarity, at least 99.9% similarity, or 100% similarity).

In some embodiments, the GABA-producing bacteria can be identified by NCBI Taxon ID of the organism they are most related to by 16S sequence. These bacteria include those belonging to the same NCBI Taxon assignment as Bacteroides caccae KLE1911; Bacteroides clarus KLE1930; Bacteroides dorei KLE1912; Bacteroides finegoldii KLE1931; Bacteroides fragilis KLE1958; Bacteroides massiliensis KLE1932; Bacteroides ovatus KLE1770; Bacteroides stercoris KLE1933; Bacteroides thetaiotaomicron KLE1934; Bacteroides uniformis KLE1913; Bacteroides vulgatus KLE1910; Bacteroides xylanisolvens KLE1935; Bifidobacterium adolescentis KLE 1879; Blautia obeum KLE1914; Blautia wexlerae KLE1916; Butyricimonas virosa KLE1938; Clostridium perfringens KLE1937; Clostridium sordellii KLE1939; Clostridium sp. KLE1862; Clostridium sp. KLE1918; Coprobacillus sp. KLE1779; Coprococcus sp. KLE1880; Dorea longicatena KLE1917; Eggerthella lenta KLE1926; Eubacterium rectale KLE1922; Gordonibacter pamelaeae KLE1915; Oscillibacter sp. KLE1928; Parabacteroides distasonis KLE2020; Parabacteroides merdae KLE1863; Ruminococcus gnavus KLE1940; Turicibacter sanguinis KLE1941, and combinations thereof.

TABLE 1 Strain name of GABA producing bacteria, and their cooresponding Seq. ID No. Strain Seq. ID No. Bacteroides caccae KLE1911 1 Bacteroides clarus KLE1930 2 Bacteroides dorei KLE1912 3 Bacteroides finegoldii KLE1931 4 Bacteroides fragilis KLE1958 5 Bacteroides massiliensis KLE1932 6 Bacteroides ovatus KLE1770 7 Bacteroides stercoris KLE1933 8 Bacteroides thetaiotaomicron KLE1934 9 Bacteroides uniformis KLE1913 10 Bacteroides vulgatus KLE1910 11 Bacteroides xylanisolvens KLE1935 12 Bifidobacterium adolescentis KLE1879 13 Blautia obeum KLE1914 14 Blautia wexlerae KLE1916 15 Butyricimonas virosa KLE1938 16 Clostridium perfringens KLE1937 17 Clostridium sordellii KLE1939 18 Clostridium sp. KLE1862 19 Clostridium sp. KLE1918 20 Coprobacillus sp. KLE1779 21 Coprococcus sp. KLE1880 22 Dorea longicatena KLE1917 23 Eggerthella lenta KLE1926 24 Eubacterium rectale KLE1922 25 Gordonibacter pamelaeae KLE1915 26 Oscillibacter sp. KLE1928 27 Parabacteroides distasonis KLE2020 28 Parabacteroides merdae KLE1863 29 Ruminococcus gnavus KLE1940 30 Turicibacter sanguinis KLE1941 31

Also disclosed herein are bacteria that are predicted to be capable of producing GABA (e.g., under physiologically relevant conditions and/or in the human gut). Bacteria are identified as being candidate GABA producing bacteria if they have encoded in their genome enzymes involved in GABA biosynthesis. In some embodiments, the bacteria that are predicted to be capable of producing GABA can be identified by having a 16S nucleic acid sequence substantially similar to the 16S sequences of reference bacteria listed in Table 2, with a Seq. ID. No. of 32-274. In some embodiments, the predicted GABA-producing bacteria can have at least 90% 16S sequence similarity to the 16S sequences given in Table 2, with a Seq. ID. No. of 32-274 (e.g., at least 91% similarity, at least 92% similarity, at least 93% similarity, at least 94% similarity, at least 95% similarity, at least 96% similarity, at least 97% similarity, at least 98% similarity, at least 99% similarity, at least 99.5% similarity, at least 99.9% similarity, or 100% similarity).

TABLE 2 Predicted GABA producing bacteria and their corresponding Seq. ID No.. Species Seq. ID No. Abiotrophia defective 32 Acetobacter okinawensis 33 Achromobacter arsenitoxydans 34 Achromobacter xylosoxidans 35 Acidovorax sp. 36 Acidovorax sp. 37 Acidovorax sp. 38 Acidovorax sp. 39 Acidovorax sp. 40 Actinoplanes friuliensis 41 Aeromonas enteropelogenes 42 Aeromonas hydrophila 43 Afipia birgiae 44 Afipia clevelandensis 45 Afipia sp. 46 Agrobacterium albertimagni 47 Agrobacterium sp. 48 Agrobacterium tumefaciens 49 Akkermansia muciniphila 50 Alcaligenes faecalis 51 Alicychphilus denitrificans 52 Alistipes finegoldii 53 Alistipes indistinctus 54 Alistipes onderdonkii 55 Alistipes putredinis 56 Alistipes shahii 57 Aquamicrobium defluvii 58 Arenimonas donghaensis 59 Arthrobacter sp. 60 Azospirillum sp. 61 Bacillus bataviensis 62 Bacillus cereus 63 Bacillus cereus 64 Bacillus endophyticus 65 Bacillus weihenstephanensis 66 Bacteroidaceae bacterium 67 Bacteroides acidifaciens 68 Bacteroides caccae 69 Bacteroides cellulosilyticus 70 Bacteroides dorei 71 Bacteroides eggerthii 72 Bacteroides finegoldii 73 Bacteroides fragilis 74 Bacteroides gallinarum 75 Bacteroides intestinalis 76 Bacteroides massiliensis 77 Bacteroides oleiciplenus 78 Bacteroides ovatus 79 Bacteroides rodentium 80 Bacteroides salyersiae 81 Bacteroides sartorii 82 Bacteroides sp. 83 Bacteroides sp. 84 Bacteroides sp. 85 Bacteroides sp. 86 Bacteroides stercoris 87 Bacteroides thetaiotaomicron 88 Bacteroides uniformis 89 Bacteroides vulgatus 90 Bacteroides xylanisolvens 91 Barnesiella intestinihominis 92 Bhargavaea cecembensis 93 Bifidobacterium adolescentis 94 Bifidobacterium angulatum 95 Bifidobacterium dentium 96 Bifidobacterium ruminantium 97 Blastococcus sp. 98 Bordetella bronchiseptica 99 Bordetella trematum 100 Bosea sp. 101 Bradyrhizobium sp. 102 Brevibacillus borstelensis 103 Brevundimonas diminuta 104 Brevundimonas naejangsanensis 105 Brucella abortus 106 Brucella melitensis 107 Brucella neotomae 108 Burkholderia mallei 109 Burkholderia multivorans 110 Carnobacterium gallinarum 111 Caulobacter crescentus 112 Caulobacter sp. 113 Cellulomonas flavigena 114 Cellulomonas sp. 115 Cellulosimicrobium cellulans 116 Cetobacterium somerae 117 Citrobacter amalonaticus 118 Cloacibacillus evryensis 119 Clostridium acetobutylicum 120 Clostridium perfringens 121 Comamonas granuli 122 Corynebacterium variabile 123 Cupriavidus basilensis 124 Cupriavidus sp. 125 Dechloromonas agitata 126 Deinococcus geothermalis 127 Delftia tsuruhatensis 128 Desulfovibrio desulfuricans 129 Desulfovibrio sp. 130 Devosia riboflavina 131 Eggerthella sp. 132 Ensifer adhaerens 133 Enterococcus casseliflavus 134 Enterococcus flavescens 135 Escherichia coli 136 Eubacterium limosum 137 Eubacterium nodatum 138 Eubacterium saphenum 139 Fusobacterium periodonticum 140 Gordonia sputi 141 Gordonia terrae 142 Gordonibacter pamelaeae 143 Halomonas stevensii 144 Halomonas titanicae 145 Hoeflea sp. 146 Intrasporangium calvum 147 Janibacter hoylei 148 Kaistia granuli 149 Kineococcus radiotolerans 150 Lactobacillus coleohominis 151 Lactobacillus plantarum 152 Lactobacillus reuteri 153 Lactococcus garvieae 154 Lactococcus lactis 155 Lautropia mirabilis 156 Leucobacter salsicius 157 Luteimonas huabeiensis 158 Magnetospirillum magnetotacticum 159 Marinobacter lipotyticus 160 Marmoricola sp. 161 Megasphaera micronuciformis 162 Megasphaera sp. 163 Mesorhizobium sp. 164 Methanobrevibacter arboriphilus 165 Methylobacterium radiotolerans 166 Methylobacterium sp. 167 Microbacterium sp. 168 Micromonospora aurantiaca 169 Mogibacterium Mogibacterium 170 Morganella morganii 171 Mycobacterium smegmatis 172 Mycobacterium sp. 173 Mycobacterium sp. 174 Mycobacterium vanbaalenii 175 Neisseria sicca 176 Neorhizobium galegae 177 Nocardia rhamnosiphila 178 Nocardiopsis alkaliphila 179 Nocardiopsis ganjiahuensis 180 Nocardiopsis synnemataformans 181 Nocardiopsis valliformis 182 Novosphingobium nitrogenifigens 183 Ochrobactrum intermedium 184 Odoribacter laneus 185 Odoribacter splanchnicus 186 Oerskovia turbata 187 Pannonibacter phragmitetus 188 Pantoea vagans 189 Parabacteroides distasonis 190 Parabacteroides goldsteinii 191 Parabacteroides johnsonii 192 Parabacteroides merdae 193 Parabacteroides sp. 194 Parabacteroides sp. 195 Paracoccus denitrificans 196 Paracoccus sp. 197 Paracoccus yeei 198 Parvimonas Parvimonas 199 Pectobacterium carotovorum 200 Phyllobacterium sp. 201 Polaromonas sp. 202 Porphyromonas bennonis 203 Proteus mirabilis 204 Providencia alcalifaciens 205 Providencia burhodogranariea 206 Providencia rettgeri 207 Pseudacidovorax intermedius 208 Pseudoalteromonas sp. 209 Pseudochrobactrum sp. 210 Pseudomonas aeruginosa 211 Pseudomonas alcaligenes 212 Pseudomonas chloritidismutans 213 Pseudomonas chlororaphis 214 Pseudomonas japonica 215 Pseudomonas knackmussii 216 Pseudomonas mendocina 217 Pseudomonas monteilii 218 Pseudomonas oleovorans 219 Pseudomonas putida 220 Pseudomonas savastanoi 221 Pseudomonas sp. 222 Pseudomonas sp. 223 Pseudomonas sp. 224 Pseudomonas sp. 225 Pseudomonas sp. 226 Pseudomonas sp. 227 Pseudomonas sp. 228 Pseudomonas sp. 229 Pseudomonas sp. 230 Pseudomonas stutzeri 231 Pseudomonas synxantha 232 Pseudomonas syringae 233 Pseudonocardia sp. 234 Ralstonia solanacearum 235 Raoultella planticola 236 Rhizobium leguminosarum 237 Rhizobium sp. 238 Rhodococcus defluvii 239 Rhodococcus pyridinivorans 240 Rikenella microfusus 241 Robinsoniella sp. 242 Roseomonas cervicalis 243 Roseomonas sp. 244 Salmonella enterica 245 Sanguibacter keddieii 246 Shewanella baltica 247 Shewanella sp. 248 Shinella zoogloeoides 249 Sphingopyxis alaskensis 250 Starkeya novella 251 Stenotrophomonas maltophilia 252 Stenotrophomonas rhizophila 253 Streptococcus thermophilus 254 Streptomyces atroolivaceus 255 Streptomyces coelicollavus 256 Streptomyces olindensis 257 Streptomyces rimosus 258 Streptomyces roseoverticillatus 259 Streptomyces sp. 260 Streptomyces sp. 261 Streptomyces sp. 262 Streptomyces sp. 263 Streptomyces sp. 264 Streptomyces sp. 265 Streptomyces sp. 266 Streptomyces toyocaensis 267 Streptomyces turgidiscabies 268 Synergistes sp. 269 Tannerella sp. 270 Thauera terpenica 271 Variovorax paradoxus 272 Variovorax sp. 273 Xanthomonas axonopodis 274

Engineered Strains

In some embodiments, bacteria can be engineered to produce GABA (e.g., under the conditions of the human gut). The bacteria can be engineered using techniques of molecular biology, or can be evolved using the process of selection to produce GABA in the human gut.

As set forth above, GABA can be produced by multiple pathways within a microbial cell. For example, GABA can be produced by the glutamate pathway, the putrescine to 4-aminobutanal pathway, the arginine to agmatine to putrescine pathway, the L-ornithine to putrescine pathway, or by a combination of pathways. In some embodiments, bacteria can be engineered to contain one or more enzymes in any one of the above pathways that can enable the bacteria to produce GABA or a necessary precursor to GABA.

A variety of different host bacteria can be engineered to produce GABA. For instance, in some embodiments, Escherichia coli Nissle 1917, can be genetically modified or selected through evolution to produce GABA. In some embodiments, the bacteria (e.g., Escherichia coli Nissle 1917) can be modified to express or overexpress glutamate decarboxylase A or glutamate decarboxylase B. The bacteria can also be made to produce GABA by one or more of the other pathways described herein.

Accordingly, in some embodiments, an engineered GABA-producing strain can be identified as having a specific enzyme encoded in its genomes. For example, the enzyme can be glutamate decarboxylase (EC 4.1.1.15); putrescine aminotransferase (EC 2.6.1.82); gamma-aminobutyraldehyde dehydrogenase (EC 1.2.1.19); arginine decarboxylase (EC 4.1.1.19); agmatinase (EC 3.5.3.11); ornithine decarboxylase (EC 4.1.1.17); or a combination thereof. In some embodiments, the GABA-producing strain can be engineered to contain an enzyme that has at least 50% similarity with with the representative sequences listed in Table 3 (e.g., at least 60% similarity, at least 70% similarity, at least 80% similarity, at least 90% similarity, at least 91% similarity, at least 92% similarity, at least 93% similarity, at least 94% similarity, at least 95% similarity, at least 96% similarity, at least 97% similarity, at least 98% similarity, at least 99% similarity, at least 99.5% similarity, at least 99.9% similarity, or 100% similarity). The enzyme classes, as identified by their Enzyme Commission (EC) numbers, are listed in Table 3.

TABLE 3 Enzymes involved in GABA-Production Pathways, and Seq. ID No. for representative sequences for each enzyme class Enzyme Seq ID No. Glutamate decarboxylase (EC 4.1.1.15) 275-279 Putrescine aminotransferase (EC 2.6.1.82) 280-284 Gamma-aminobutyraldehyde dehydrogenase (EC 1.2.1.19) 285-289 Arginine decarboxylase (EC 4.1.1.19) 290-294 Agmatinase (EC 3.5.3.11) 295-299 Ornithine decarboxylase (EC 4.1.1.17) 300-304

Representative examples of glutamate decarboxylase (EC 4.1.1.15) are given below in Table 4 and identified by their EMBL/GENBANK/DDBJ ID numbers. Any of the bacteria given in Table 10 can be engineered with any version of the glutamate decarboxylase set forth in Table 3 or Table 4. For instance, the bacteria can be engineered with a version of the glutamate decarboxylase enzyme that has at least 50% nucleotide similarity with any of the versions of glutamate decarboxylase given in Table 4 (e.g., at least nucleotide 60% similarity, at least 70% nucleotide similarity, at least 80% nucleotide similarity, at least 90% nucleotide similarity, at least 91% nucleotide similarity, at least 92% nucleotide similarity, at least 93% nucleotide similarity, at least 94% nucleotide similarity, at least 95% nucleotide similarity, at least 96% nucleotide similarity, at least 97% nucleotide similarity, at least 98% nucleotide similarity, at least 99% nucleotide similarity, at least 99.5% nucleotide similarity, at least 99.9% nucleotide similarity, or 100% nucleotide similarity).

TABLE 4 Representative Examples of Glutamate Decarboxylase by EMBL/GENBANK/DDBJ ID Number AAA23833.1 ABF03896.1 ABV88270.1 ADI09031.1 AAA23834.1 ABF05994.1 ABV98199.1 ADJ50560.1 AAB18493.1 ABF08645.1 ABW16238.1 ADM42706.1 AAC46188.1 ABG57877.1 ABY23810.1 ADN37174.1 AAC74566.1 ABG82826.1 ABY39350.1 ADO35975.1 AAC76542.1 ABG85385.1 ABZ77591.1 ADP83065.1 AAG22560.1 ABG97793.1 ABZ87126.1 ADR26899.1 AAG22562.1 AB147454.1 ACA46668.1 ADR28903.1 AAG56275.1 ABJ00921.1 ACA53668.1 ADT67741.1 AAG58658.1 ABJ02999.1 ACA88989.1 ADT75096.1 AAK05388.1 ABJ63253.1 ACB15780.1 ADT77123.1 AAK17187.1 ABJ64910.1 ACB15938.1 ADU00909.1 AAK47878.1 ABK67541.1 ACC39574.1 ADU26301.1 AAL54152.1 ABK75920.1 ACD04211.1 ADW04875.1 AAL54153.1 ABK90558.1 ACD07724.1 ADY32347.1 AAN43309.2 ABL03510.1 ACD82162.1 ADY58934.1 AAN45045.2 ABL90375.1 ACH65664.1 ADY59978.1 AAN54823.2 ABM09145.1 ACJ29997.1 ADZ09662.1 AAN80380.1 ABM12315.1 ACL47965.1 ADZ09880.1 AAN82764.1 ABM78546.1 ACN16811.1 AEA24253.1 AAO77677.1 ABP47401.1 ACO85906.1 AEA24271.1 AAP17196.1 ABP56802.1 ACR68120.1 AEB72391.1 AAP19142.1 ABQ62050.1 ACS81597.1 AEE27076.1 AAS06807.1 ABQ75258.1 ACU49468.1 AEE56495.1 AAS41604.1 ABQ85037.1 ACU54556.1 AEE58814.1 AAT42735.1 ABQ85038.1 ACU77475.1 AEF37245.1 AAW85387.1 ABQ85039.1 ACV54143.1 AEF40931.1 AAW85559.1 ABQ85040.1 ACV81603.1 AEG17214.1 AAZ71647.1 ABQ85043.1 ACY51919.1 AEH47920.1 AAZ88326.1 ABQ85046.1 ACY85701.1 AEH93409.1 AAZ90121.1 ABQ85049.1 ADA65034.1 AEH93479.1 ABB61740.1 ABQ85050.1 ADA74124.1 AE135432.1 ABB63509.1 ABQ85051.1 ADA75905.1 AEJ56545.1 ABB66175.1 ABQ85053.1 ADB10338.1 AEJ58918.1 ABB68000.1 ABQ85058.1 ADB51885.1 AEK38321.1 ABC77952.1 ABR41498.1 ADD56429.1 AEK47566.1 ABD09573.1 ABR42591.1 ADD58723.1 AEK58322.1 ABE07185.1 ABS42061.1 ADE69489.1 AEM48695.1 ABE09478.1 ABU72013.1 ADF39290.1 AEM88213.1 ABE29172.1 ABV20447.1 ADG78237.1 AEN10737.1 ABE36450.1 ABV20705.1 ADG96760.1 AEN89628.1 AEO05457.1 AGC43105.1 AHY70401.1 AJD30517.1 AEO07341.1 AGC61247.1 AHY72977.1 AJE06383.1 AEO07410.1 AGE37597.1 AHZ23367.1 AJE12001.1 AEQ12485.1 AGF77926.1 AIA01950.1 AJE41795.1 AEQ14770.1 AGG29530.1 AIA05032.1 AJE55882.1 AET90796.1 AGJ55746.1 AIA30132.1 AJE58075.1 AEU40604.1 AGK78014.1 AIA55291.1 AJE83295.1 AEU40605.1 AGK95653.1 AIIA73764.1 AJE87567.1 AEV39535.1 AGL28896.1 AIC75915.1 AJF56325.1 AEV71230.1 AGL89003.1 AIE75400.1 AJF58318.1 AEV85044.1 AGM10224.1 AIE79640.1 AJF66001.1 AEW99357.1 AGM23454.1 AIIG80748.1 AJG19558.1 AEY90789.1 AGM30354.1 AII05027.1 AJG22402.1 AFA40032.1 AGN85370.1 AII76842.1 AJG22403.1 AFA47141.1 AGO09336.1 AIJ07554.1 AJG93936.1 AFA74414.1 AGP31884.1 AIJ15081.1 AJH17760.1 AFC23797.1 AGP56881.1 AIJ26745.1 AJI06057.1 AFC45457.1 AGP65818.1 AIR16227.1 AJI25468.1 AFG40494.1 AGR65020.1 AIS03708.1 AJI52230.1 AFG42464.1 AGS70940.1 AIS31569.1 AJI53611.1 AFJ28998.1 AGV73208.1 AIS60683.1 AJI57942.1 AFJ31191.1 AGY44310.1 AIS60750.1 AJI68933.1 AFJ37206.1 AGZ52354.1 AIT09528.1 AJI74183.1 AFK19988.1 AHA64741.1 AIU74973.1 AJI88044.1 AFK57885.1 AHA64994.1 AIX63299.1 AJJ46763.1 AFL79172.1 AHA67486.1 AIX65458.1 AJK40118.1 AFM15894.1 AHA67487.1 AIY00711.1 AJK45246.1 AFN45150.1 AHD20397.1 AIY45527.1 AJO83482.1 AFP38009.1 AHE48317.1 AIY83613.1 AJO85575.1 AFR07193.1 AHE57937.1 AIY84119.1 AJQ91926.1 AFR30984.1 AHE60304.1 AIZ82546.1 AJT65391.1 AFR47006.1 AHF05109.1 AIZ84546.1 AJW41655.1 AFS16303.1 AHF13271.1 AJA19876.1 AJY44977.1 AFS52965.1 AHG20573.1 AJA25926.1 AKB18082.1 AFS74495.1 AHH15398.1 AJA28548.1 AKB18368.1 AFT98587.1 AHH98082.1 AJA57089.1 AKB21414.1 AFV89643.1 AHJ76938.1 AJA79136.1 AKB22089.1 AFY29504.1 AHK29878.1 AJA80033.1 AKB28570.1 AFZ52375.1 AHM72117.1 AJC56876.1 AKB32481.1 AGA90199.1 AHW62584.1 AJC60332.1 AKB36808.1 AGB21530.1 AHX21760.1 AJD29942.1 AKB44521.1 AKB48030.1 ANP20338.1 BAN07465.1 CBG71067.1 AKB51234.1 AOM43274.1 BAN32855.1 CBH50652.1 AKB54327.1 AOM46217.1 BAO88345.1 CBJ01067.1 AKB57594.1 AOM69863.1 CAA44834.1 CBJ03264.1 AKB78420.1 AOM72020.1 CAA50736.1 CBJ13441.1 AKB81570.1 AOT30761.1 CAB42769.1 CBK63002.1 AKC40119.1 AOT32983.1 CAC97690.1 CBK66783.1 AKD98129.1 APA40105.1 CAC97755.1 CBL04696.1 AKF85158.1 APA42487.1 CAC98526.1 CBL57837.1 AKG70083.1 APA95425.1 CAD00441.1 CBW21055.1 AKG72082.1 BAA15163.1 CAD00512.1 CBW86770.1 AKH24178.1 BAA17064.1 CAE20649.1 CBW86835.1 AKH26551.1 BAA24585.1 CAE33151.1 CBY25615.1 AKH83393.1 BAA30034.1 CAG35114.1 CBY25616.1 AKJ11706.1 BAB35521.1 CAG46355.1 CBY83732.1 AKK26454.1 BAB37820.1 CAH06161.1 CCA56552.1 AKK48189.1 BAB81764.1 CAJ13031.1 CCB79422.1 AKK50365.1 BAC71313.1 CAJ13032.1 CCB79423.1 AKL69083.1 BAC72367.1 CAJ50408.1 CCC28516.1 AKM35002.1 BAD47203.1 CAK21799.1 CCC45780.1 AKM37064.1 BAD58388.1 CAK28447.1 CCC80401.1 AKN61935.1 BAE77777.1 CAL13720.1 CCF80014.1 AKN70627.1 BAG20906.1 CAL73487.1 CCF80015.1 AKP77446.1 BAG77107.1 CAL97772.1 CCG87871.1 AKQ55619.1 BAG79310.1 CAM63814.1 CCG91229.1 AKR03347.1 BAH34246.1 CAQ78882.1 CCG98062.1 AKS23002.1 BAH54322.1 CAQ89093.1 CCH30995.1 ALD25331.1 BAI25363.1 CAQ90311.1 CCH77936.1 ALL88386.1 BAI27772.1 CAR02896.1 CCH93070.1 ALL90542.1 BAI30441.1 CAR05140.1 CCH98079.1 ALZ68108.1 BAI32950.1 CAR07836.2 CCI01250.1 AMC47930.1 BAI35784.1 CAR10182.1 CCI09506.1 AMW41208.1 BAI38094.1 CAR12949.1 CCI18860.1 AMW43303.1 BAJ28326.1 CAR15161.1 CCI27064.1 AMX13814.1 BAJ74886.1 CAR17889.1 CCJ46136.1 AMX15691.1 BAK43421.1 CAR20131.1 CCJ52392.1 ANK32168.1 BAL67532.1 CAR42970.1 CCK19015.1 ANM82251.1 BAL89884.1 CAS09168.1 CCK19016.1 ANM84279.1 BAM06654.1 CAS11307.1 CCK28448.1 ANO91466.1 BAM50779.1 CAU97478.1 CCK46704.1 ANP18008.1 BAN05709.1 CAV00414.1 CCK48823.1 CCK79225.1 CEJ51402.1 CRG01912.1 EAR53494.1 CCO09825.2 CEK27848.1 CRH16097.1 EAS62995.1 CCO10173.1 CEK31257.1 CRH16918.1 EAU72855.1 CCO13002.2 CEK34473.1 CRH16922.1 EAV43522.1 CCO24580.1 CEK36954.1 CRI32384.1 EDK88619.1 CCO64903.1 CEL25420.1 CRI34932.1 EDL53816.1 CCO64970.1 CEO8246.1 CRK49247.1 EDL54868.1 CCP46254.1 CEP25754.1 CRK49766.1 EDL56435.1 CCQ12644.1 CEP41466.1 CRY53884.1 EDL68777.1 CCQ14157.1 CEQ04848.1 CRY55938.1 EDM21919.1 CCW09328.1 CEQ04850.1 CRY74150.1 EDM65095.1 CCW10939.1 CFE36737.1 CRZ15952.1 EDN56728.1 CDG05069.1 CFE50785.1 CSK83327.1 EDN71351.1 CDG65008.1 CFQ66985.1 CSK89516.1 EDN82399.1 CDI46519.1 CFT98680.1 CSN37587.1 EDN85024.1 CDK01888.1 CFT98693.1 CSN43893.1 EDO14168.1 CDK72542.1 CKO74072.1 CSP86321.1 EDO51732.1 CDK77522.1 CKR41672.1 CSS74791.1 EDP24277.1 CDL24770.1 CKR63720.1 CTQ53252.1 EDP59239.1 CDL26737.1 CKR87162.1 CTQ71526.1 EDS02296.1 CDL29747.1 CKV41513.1 CTT09685.1 EDS16532.1 CDM06669.1 CNH63762.1 CTT19248.1 EDS80418.1 CDM06670.1 CNN53125.1 CTT51717.1 EDS92014.1 CDN82039.1 CNZ28847.1 CTT83594.1 EDS93501.1 CDN84269.1 COF20080.1 CTU03723.1 EDT12835.1 CDO09876.1 COQ21776.1 CTU48438.1 EDT15330.1 CDO20324.1 COR80523.1 CTU63923.1 EDT25330.1 CDO27974.1 COV15812.1 CTV28671.1 EDT73179.1 CDO44733.1 COV67826.1 CTV69168.1 EDU36907.1 CDO87126.1 COV88060.1 CTW64116.1 EDU39421.1 CDP84850.1 COW22072.1 CTX10177.1 EDU64919.1 CDQ46433.1 COW50746.1 CTZ19187.1 EDU66726.1 CDR08766.1 COW69018.1 CTZ24614.1 EDU90194.1 CDU38691.1 CPR27659.1 CTZ73544.1 EDU92849.1 CDY74306.1 CPR27660.1 CTZ73631.1 EDV04249.1 CDZ89912.1 CQD07112.1 CUJ14933.1 EDX35836.1 CEA13064.1 CRF40589.1 CUK00697.1 EDX36856.1 CED70967.1 CRF42243.1 CUO21357.1 EDX42043.1 CEF51573.1 CRF44683.1 EAO55448.1 EDY39693.1 CEG58623.1 CRF48464.1 EAQ75094.1 EDY48172.1 CEI23431.1 CRF50704.1 EAQ80748.1 EDY57831.1 EDY66556.1 EEV56374.1 EFH84743.1 EFK90538.1 EDZ49153.1 EEW54005.1 EFI02264.1 EFL01709.1 EEA85567.1 EEW82128.1 EFI09603.1 EFL11602.1 EEA92251.1 EEX25513.1 EFI13088.1 EFL25055.1 EEB26629.1 EEX36940.1 EFI38206.1 EFL33863.1 EEB44239.1 EEX43978.1 EFI84887.1 EFL40837.1 EEC53338.1 EEY24480.1 EFI86925.1 EFL51206.1 EEC97976.1 EEY27756.1 EFI90012.1 EFM42529.1 EEE44061.1 EEY43805.1 EFJ64163.1 EFM60472.1 EEF92068.1 EEY85097.1 EFJ67574.1 EFO55353.1 EEH13682.1 EEZ00407.1 EFJ67825.1 EFO56156.1 EE148912.1 EEZ01978.1 EFJ70740.1 EFO57476.1 EEK47458.1 EEZ22076.1 EFJ74790.1 EFP68935.1 EEK58881.1 EEZ25940.1 EFJ79351.1 EFP72276.1 EEK67538.1 EEZ29262.1 EFJ83178.1 EFP94638.1 EEK74538.1 EEZ34469.1 EFJ84244.1 EFQ03510.1 EEL55986.1 EEZ40302.1 EFJ97064.1 EFQ52308.1 EEL62126.1 EEZ87328.1 EFJ99289.1 EFR14005.1 EEL64999.1 EFA19754.1 EFK00002.1 EFR14897.1 EEL67614.1 EFB70565.1 EFK01991.1 EFR53885.1 EEM80145.1 EFC83076.1 EFK04591.1 EFR56886.1 EEN88413.1 EFD80779.2 EFK05907.1 EFR83644.1 EEO04360.1 EFE24383.1 EFK13346.1 EFR86795.1 EEO15980.1 EFE51558.1 EFK13449.1 EFR86868.1 EEO27017.1 EFE61154.2 EFK18567.1 EFR99235.1 EEO29218.1 EFE67958.2 EFK21645.1 EFS34161.1 EEO44870.1 EFE75545.2 EFK25237.1 EFU32132.1 EEO51903.1 EFE80893.2 EFK26359.1 EFU32541.1 EEO53210.1 EFE85357.2 EFK27490.1 EFU33441.1 EEO59155.1 EFF04255.2 EFK28268.1 EFU33881.1 EEP21189.1 EFF12025.2 EFK45013.1 EFV13462.1 EEP92210.1 EFF50165.1 EFK46521.1 EFV25334.1 EEQ11471.1 EFF76031.1 EFK48488.1 EFV31182.1 EES66073.1 EFF93925.2 EFK53224.1 EFV39052.1 EET14820.1 EFG07494.1 EFK62734.1 EFV65675.1 EEU03858.1 EFG18425.1 EFK65701.1 EFW48115.1 EEU29590.1 EFG35990.2 EFK67634.1 EFW51528.1 EEU51973.1 EFG64869.2 EFK74425.1 EFW54250.1 EEV32935.1 EFG76193.1 EFK74957.1 EFW54681.1 EEV37488.1 EFH79810.1 EFK75509.1 EFW58324.1 EEV50802.1 EFH81299.1 EFK90487.1 EFW59607.1 EGB59643.1 EGN06817.1 EHU11189.1 EII44135.1 EGB61475.1 EGN63303.1 EHU13384.1 EII46969.1 EGB64139.1 EGP19624.1 EHU15660.1 EIL45389.1 EGB66614.1 EGQ80440.1 EHU18453.1 EIQ03265.1 EGB70190.1 EGU29737.1 EHU18784.1 EIQ09746.1 EGB73425.1 EGU35278.1 EHU21355.1 EIQ16517.1 EGB88811.1 EGU39626.1 EHU24375.1 EIQ21777.1 EGB89514.1 EGU97184.1 EHU24577.1 EIQ23262.1 EGB90401.1 EGU98834.1 EHU31058.1 EIQ25087.1 EGB91657.1 EGV18719.1 EHU32272.1 EIQ31493.1 EGC70448.1 EGV27688.1 EHU34561.1 EIQ33054.1 EGC88487.1 EGX55742.1 EHU41140.1 EIQ41164.1 EGC95220.1 EHA59342.1 EHU45989.1 EIQ56419.1 EGC96302.1 EHB58351.1 EHU51025.1 EIQ60911.1 EGD21507.1 EHB91964.1 EHU59824.1 EIQ65585.1 EGD55026.1 EHD14624.1 EHV53301.1 EIQ73835.1 EGE43685.1 EHE93619.1 EHV59537.1 EIV94746.1 EGF51021.1 EHE94113.1 EHY69914.1 EIY16248.1 EGF52343.1 EHE94521.1 EIC22952.1 EIY32949.1 EGG47377.1 EHG27891.1 EID17062.1 EIY34626.1 EGI12229.1 EHI10396.1 EID62180.1 EIY38162.1 EGI13717.1 EHI78992.1 EID64225.1 EIY53226.1 EGI13978.1 EHJ93424.1 EID65429.1 EIY53668.1 EGI17642.1 EHK60317.1 EID81668.1 EIY56384.1 EGI19234.1 EHK80663.1 EIF28258.1 EIY56765.1 EGI21026.1 EHL31595.1 EIF91592.1 EIY68174.1 EGI39093.1 EHL69790.1 EIG81214.1 EIY77090.1 EGI43841.1 EHL73453.1 EIG83636.1 EIY82381.1 EGI50973.1 EHL81956.1 EIG91092.1 EIY84200.1 EGI90408.1 EHM02181.1 EIG94667.1 EIY99194.1 EGI96641.1 EHM25499.1 EIH12190.1 EIZ01495.1 EGI99727.1 EHN10689.1 EIH14542.1 EJC61553.1 EGJ08652.1 EHN62296.1 EIH23819.1 EJE70343.1 EGJ75615.1 EHN62769.1 EIH24646.1 EJE81777.1 EGK16006.1 EHN72080.1 EIH44138.1 EJF49319.1 EGK24662.1 EHO78886.1 EIH44293.1 EJF70133.1 EGK37777.1 EHP50963.1 EIH77187.1 EJI94816.1 EGL35452.1 EHP65728.1 EIH78539.1 EJJ06689.1 EGM70497.1 EHQ35549.1 EII21895.1 EJL12446.1 EGM97167.1 EHS85882.1 EII32183.1 EJL17356.1 EGM98872.1 EHU04987.1 EII37008.1 EJO88499.1 EJQ45735.1 EKT59853.1 EME15609.1 ENA07939.1 EJQ50924.1 EKT60979.1 EME20496.1 ENA37276.1 EJQ75845.1 EKT61230.1 EME52937.1 ENA37661.1 EJR29226.1 EKT84064.1 EME64490.1 ENA40409.1 EJR29527.1 EKU27305.1 EMF01384.1 ENA42821.1 EJR54172.1 EKU87970.1 EMF28280.1 ENA44156.1 EJR72119.1 EKZ99806.1 EMF57186.1 ENA45677.1 EJS51805.1 ELB02396.1 EMI07274.1 ENA45982.1 EJS69263.1 ELB85708.1 EMI44202.1 ENC88982.1 EJS76732.1 ELC09056.1 EMI57857.1 ENC89168.1 EJU20276.1 ELC13735.1 EMP52368.1 ENC92105.1 EJV56692.1 ELC15832.1 EMQ97025.1 END50208.1 EJV88830.1 ELC19797.1 EMS71451.1 END53674.1 EJZ11766.1 ELC36081.1 EMS81015.1 END88206.1 EJZ58218.1 ELC41591.1 EMT34264.1 END92583.1 EJZ61626.1 ELC88436.1 EMU58101.1 END93094.1 EJZ66136.1 ELC95019.1 EMU62217.1 ENG91208.1 EJZ66990.1 ELD95713.1 EMU62585.1 ENG94444.1 EKA79028.1 ELE00848.1 EMU62751.1 ENG94576.1 EKA86551.1 ELE39573.1 EMU66940.1 ENG97999.1 EKA88098.1 ELE43669.1 EMU67068.1 ENG99381.1 EKA94470.1 ELE52314.1 EMU70180.1 ENG99667.1 EKC91611.1 ELE55503.1 EMV16365.1 ENH03300.1 EKC92880.1 ELE57206.1 EMV16410.1 ENH06479.1 EKF24812.1 ELE60967.1 EMV21034.1 ENH06612.1 EKI49243.1 ELG85654.1 EMV21148.1 ENH09530.1 EKI49295.1 ELG89467.1 EMW92532.1 ENT93039.1 EKI49297.1 ELP68892.1 EMW92626.1 ENZ87560.1 EKI53609.1 ELQ79669.1 EMX05363.1 EOA56991.1 EKI53635.1 ELQ90802.1 EMX05478.1 EOA59672.1 EKI53661.1 ELS31036.1 EMX17914.1 EOD68466.1 EKJ88854.1 ELS48492.1 EMX21187.1 EOD79253.1 EKM22885.1 ELS55266.1 EMX28781.1 EOH72070.1 EKN10373.1 ELU51445.1 EMX32419.1 EOH74810.1 EKN12672.1 ELV08451.1 EMX35642.1 EOH75851.1 EKN18388.1 ELW26442.1 EMX40966.1 EOH76700.1 EKN22714.1 ELW30245.1 EMX45867.1 EOH78743.1 EKN32408.1 ELW35612.1 EMX49551.1 EOH82280.1 EKN33078.1 ELW38629.1 EMX82482.1 EOH83172.1 EKN71286.1 ELZ99535.1 EMX88290.1 EOH97586.1 EKT54086.1 EMD22949.1 ENA02373.1 EOI53551.1 EOI58405.1 EOU96296.1 EQK38916.1 ERL43390.1 EOI58566.1 EOV01967.1 EQK38918.1 ERM89976.1 EOM77145.1 EOV09633.1 EQK41183.1 ERN40441.1 EON30602.1 EOV50262.1 EQK41185.1 ERP96019.1 EOO14854.1 EOV53815.1 EQK41187.1 ERT35460.1 EOO21616.1 EOV63027.1 EQK44497.1 ERT41208.1 EOO5486.1 EOV75070.1 EQK44499.1 ERT49556.1 EOO35817.1 EOV79548.1 EQM30718.1 ERT62990.1 EOO41016.1 EOV87732.1 EQM34161.1 ESA62393.1 EOO43604.1 EOV92823.1 EQM76570.1 ESA65687.1 EOO45684.1 EOW02331.1 EQN22922.1 ESA66394.1 EOO62333.1 EOW07796.1 EQN27974.1 ESA93675.1 EOO80321.1 EOW18421.1 EQN90009.1 ESC98980.1 EOP01042.1 EOW20754.1 EQN99753.1 ESD24585.1 EOP10173.1 EOW24078.1 EQO57355.1 ESD76492.1 EOP26670.1 EOW28567.1 EQO68196.1 ESE01639.1 EOP64330.1 EOW59950.1 EQP45261.1 ESE85174.1 EOP73916.1 EOW65871.1 EQP56441.1 ESK09396.1 EOQ08142.1 EOW93464.1 EQQ01715.1 ESK17280.1 EOQ12252.1 EOW98321.1 EQQ13272.1 ESK32677.1 EOQ46471.1 EPD56434.1 EQV93401.1 ESK37118.1 EOQ66882.1 EPH07228.1 EQV95026.1 ESL01761.1 EOR96931.1 EPH19749.1 EQX25160.1 ESN63984.1 EOS04353.1 EPH46070.1 EQX28194.1 ESQ03366.1 EOS05800.1 EPH62839.1 EQX84913.1 ESS01667.1 EOS12272.1 EPH66025.1 EQX88348.1 EST27229.1 EOS15404.1 EPH93813.1 EQY14917.1 EST29520.1 EOS50628.1 EP124085.1 EQY25002.1 EST30199.1 EOT40719.1 EPJ40403.1 EQY56854.1 EST38278.1 EOT40879.1 EPJ94947.1 EQY62408.1 ESU48041.1 EOT47239.1 EPZ46100.1 EQZ97993.1 ESW58026.1 EOT48800.1 EPZ53654.1 ERA02674.1 ETA03730.1 EOT84227.1 EPZ62416.1 ERB52265.1 ETA07612.1 EOT87490.1 EPZ62425.1 ERB55118.1 ETA90193.1 EOU43828.1 EPZ62435.1 ER140669.1 ETB03602.1 EOU46128.1 EPZ62442.1 ERK10135.1 ETB08300.1 EOU63366.1 EPZ62447.1 ERK12938.1 ETB10179.1 EOU68068.1 EQC78775.1 ERK13614.1 ETB16733.1 EOU81074.1 EQC92431.1 ERK41051.1 ETB35297.1 EOU84041.1 EQI12458.1 ERK66628.1 ETB47280.1 EOU87778.1 EQK38915.1 ERK71783.1 ETD05566.1 ETD33178.1 EWM15117.1 EZD95411.1 GAC16640.1 ETD61117.1 EWM60131.1 EZE53483.1 GAC19112.1 ETE20971.1 EWS92576.1 EZE53678.1 GAC24811.1 ETE21708.1 EWT00088.1 EZJ35629.1 GAC28020.1 ETE42297.1 EXG78068.1 EZJ35909.1 GAC32436.1 ETI67406.1 EXJ13320.1 EZJ42565.1 GAC47684.1 ETO95552.1 EXU65898.1 EZJ48607.1 GAC52174.1 ETT01291.1 EXU86004.1 EZJ48835.1 GAC57015.1 ETT07691.1 EXU92348.1 EZJ52118.1 GAC62570.1 ETT26644.1 EXY29077.1 EZJ52194.1 GAC65427.1 ETW26102.1 EXY29706.1 EZJ63265.1 GAC68386.1 ETY41349.1 EXY30556.1 EZJ68808.1 GAC80779.1 ETY48295.1 EXY42580.1 EZJ76944.1 GAC84962.1 ETY71896.1 EXY67115.1 EZJ82498.1 GAD02073.1 ETZ28153.1 EXY71894.1 EZJ83430.1 GAD32959.1 ETZ53554.1 EXY75839.1 EZJ85518.1 GAD74177.1 ETZ64519.1 EXY86423.1 EZJ86304.1 GAD82821.1 EUA15396.1 EXY92402.1 EZJ86635.1 GAF38011.1 EUA21463.1 EXZ07152.1 EZJ86695.1 GAF50854.1 EUA28413.1 EXZ21187.1 EZK23505.1 GAJ68231.1 EUA53026.1 EXZ30272.1 GAA03253.1 GAJ81697.1 EUA67104.1 EXZ46400.1 GAA12812.1 GAK24408.1 EUA75069.1 EXZ75157.1 GAA58630.1 GAK28408.1 EUA92002.1 EXZ80321.1 GAA65880.1 GAK83740.1 EUB26488.1 EXZ85038.1 GAA68572.1 GAK86157.1 EUB31643.1 EXZ96661.1 GAA78749.1 GAK86158.1 EUB36799.1 EYA21095.1 GAA78750.1 GAK86159.1 EUC52448.1 EYA40854.1 GAB03735.1 GAK86194.1 EUC78743.1 EYB10940.1 GAB11197.1 GAK86195.1 EUD07003.1 EYD86105.1 GAB17583.1 GAL07170.1 EUJ23680.1 EYE48014.1 GAB22060.1 GAL07171.1 EUJ28388.1 EYE57289.1 GAB34314.1 GAL12019.1 EUJ30749.1 EYT59609.1 GAB40201.1 GAL12020.1 EUJ31401.1 EYT64496.1 GAB42886.1 GAL12022.1 EUJ40784.1 EYT82998.1 GAB44706.1 GAL20988.1 EUJ40792.1 EYU71182.1 GAB56771.1 GAL20989.1 EUJ41071.1 EYV06431.1 GAB57270.1 GAL29483.1 EUJ42403.1 EYZ98625.1 GAB87450.1 GAL29484.1 EUJ43336.1 EZA00512.1 GAB93700.1 GAL31575.1 EUJ51856.1 EZA34652.1 GAC00312.1 GAL31576.1 EWC60294.1 EZA36855.1 GAC07309.1 GAL34169.1 GAL35839.1 KDP04362.1 KEN52247.1 KFZ83979.1 GAL35840.1 KDQ00107.1 KEN57490.1 KGA45423.1 GAL35841.1 KDQ03697.1 KEN61954.1 KGA59562.1 GAL87714.1 KDQ68019.1 KEN64216.1 KGA94282.1 GAL92165.1 KDR43957.1 KEN69872.1 KGE62311.1 GAM51354.1 KDS10818.1 KEN70466.1 KGI67105.1 GAM53981.1 KDS15451.1 KEN96761.1 KGI75049.1 GAM59058.1 KDS30703.1 KEN96869.1 KGJ48506.1 GAM59059.1 KDS50373.1 KEO01826.1 KGJ48508.1 GAM60805.1 KDS51190.1 KEO06704.1 KGL37357.1 GAM66966.1 KDS54295.1 KEO12265.1 KGL37365.1 GAM66967.1 KDS68998.1 KEO12361.1 KGL42766.1 GAM71689.1 KDU28500.1 KEO27842.1 KGL45419.1 GAM71690.1 KDV27639.1 KEO34740.1 KGL45426.1 GAM71691.1 KDV35035.1 KEO53821.1 KGM61473.1 GAM74761.1 KDV65274.1 KEQ19823.1 KGM61755.1 GAM76677.1 KDW28640.1 KER51036.1 KGM69566.1 GAM76678.1 KDW31269.1 KER76820.1 KGM78904.1 GAM76679.1 KDX16969.1 KES06427.1 KGM81894.1 GAM80335.1 KDX18273.1 KEY62213.1 KGM84341.1 GAM80336.1 KDX19058.1 KEZ81504.1 KGM85121.1 GAM95569.1 KDX19100.1 KFA95398.1 KGP43353.1 GAO06850.1 KDX37004.1 KFA95888.1 KGQ70005.1 GAP74509.1 KEF97907.1 KFC84707.1 KGR34277.1 KBR62640.1 KEG40867.1 KFC90678.1 KHE42794.1 KBZ68706.1 KEI69530.1 KED42951.1 KHI28202.1 KCV62158.1 KEI99750.1 KED43242.1 KHJ22054.1 KDA43821.1 KEJ44146.1 KED74162.1 KHJ71931.1 KDA56308.1 KEJ48094.1 KED78258.1 KHJ73332.1 KDA58506.1 KEJ57806.1 KFE40611.1 KHK01750.1 KDD64269.1 KEJ63339.1 KFF59575.1 KHK96657.1 KDE11380.1 KEJ72299.1 KFF94854.1 KHK97208.1 KDE98800.1 KEJ77438.1 KFF96973.1 KHL05645.1 KDG91983.1 KEJ77524.1 KFI71515.1 KHM48596.1 KDG95757.1 KEJ87021.1 KFI90825.1 KHO23213.1 KDN16332.1 KEK13730.1 KFI97074.1 KHO27057.1 KDN21808.1 KEK28691.1 KFJ42086.1 KHS42788.1 KDN77775.1 KEL66215.1 KFJ73865.1 KIA60405.1 KDN85633.1 KEL67246.1 KFK85587.1 KIA71170.1 KDO93455.1 KEL68023.1 KFK95245.1 KIC39052.1 KDP03104.1 KEL70025.1 KFX75687.1 KIC69438.1 KIC99691.2 KJF96745.1 KLD60995.1 KMQ76627.1 KID43237.1 KJG19354.1 KLE26826.1 KMS68506.1 KID43894.1 KJG35319.1 KLI09651.1 KMS83576.1 KIE05689.1 KJG55556.1 KLI91468.1 KMT54476.1 KIIE57897.1 KJK37053.1 KLI98112.1 KMV17260.1 KIF05904.1 KJK56361.1 KLJ05152.1 KMV23624.1 KIF45347.1 KJL18343.1 KLN34163.1 KMW38818.1 KIF54655.1 KJL32904.1 KLN95712.1 KMW82598.1 KIF68652.1 KJL38091.1 KLO25668.1 KNA39120.1 KIG96197.1 KJL44323.1 KLO35668.1 KNA42305.1 KII76501.1 KJS62465.1 KLO43396.1 KNA42530.1 KIM01026.1 KJU70415.1 KLO51710.1 KNB52133.1 KIM15962.1 KJW12820.1 KLR49798.1 KNC11996.1 KIO34904.1 KJW22772.1 KLR60461.1 KND28891.1 KIO44976.1 KJW44373.1 KLU05222.1 KND38179.1 KIO94387.1 KJY18848.1 KLU19162.1 KND38376.1 KIO96271.1 KJY30329.1 KLU58975.1 KND61615.1 KIP30337.1 KJY38629.1 KLU69060.1 KNF63080.1 KIP53570.1 KJY39390.1 KLV28432.1 KNF82369.1 KIP73611.1 KJY40940.1 KLX53926.1 KNH21214.1 KIQ19345.1 KJY43460.1 KLX61120.1 KNZ42189.1 KIQ45943.1 KKA40192.1 KLX94454.1 KOA33258.1 KIQ62037.1 KKB46833.1 KLX97537.1 KOA34702.1 KIQ77066.1 KKB57083.1 KME63659.1 KOG31486.1 KIQ77348.1 KKB58027.1 KME67053.1 KOG36523.1 KIS21947.1 KKC03154.1 KME68735.1 KOG41666.1 KIS23847.1 KKD05819.1 KMM25249.1 KOG45278.1 KIU16352.1 KKD45841.1 KMM34481.1 KOG56200.1 KIV73177.1 KKD49597.1 KMM81854.1 KOG63866.1 KIX49302.1 KKD62061.1 KMM85123.1 KOG67868.1 KIZ19716.1 KKE98190.1 KMM89123.1 KOG82155.1 KIZ46656.1 KKI22291.1 KMN03094.1 KON11130.1 KJE22572.1 KKI42113.1 KMN10907.1 KON74404.1 KJE77520.1 KKI50839.1 KMN15408.1 KON83792.1 KJF18813.1 KKW62398.1 KMN18102.1 KOP74641.1 KJF19781.1 KKX97583.1 KMN42082.1 KOR26641.1 KJF19871.1 KKY01177.1 KMN99021.1 KOS58051.1 KJF23624.1 KKY01179.1 KMO68962.1 KOT30645.1 KJF79218.1 KKY69347.1 KMO71467.1 KOT53033.1 KJF79887.1 KLA29488.1 KMO77249.1 KOT88922.1 KJF93058.1 KLA31120.1 KMO96783.1 KOT94882.1 KOU20397.1 KOY49525.1 KPN18694.1 KQJ27665.1 KOU22686.1 KOY53494.1 KPN43081.1 KST35322.1 KOU33149.1 KOY54178.1 KPN48420.1 KST82806.1 KOU50755.1 KPA51275.1 KPO13719.1 KST89062.1 KOU54733.1 KPC66018.1 KPO16265.1 KSU11406.1 KOU56607.1 KPC77424.1 KPO16391.1 KSU16536.1 KOV13964.1 KPC82004.1 KPO17089.1 KXL66213.1 KOV45494.1 KPD04524.1 KPO34510.1 KYR53955.1 KOV48801.1 KPG33268.1 KPO35845.1 KYV67232.1 KOV52774.1 KPH96934.1 KPO37368.1 KYV71371.1 KOV57805.1 KPI04468.1 KPO41178.1 OAJ87252.1 KOV68117.1 KPI10516.1 KPO44233.1 OAJ89593.1 KOV68430.1 KPI15295.1 KPO51751.1 OAO63316.1 KOV76057.1 KPI19262.1 KPO52539.1 OCL17438.1 KOV97628.1 KPI20012.1 KPO58193.1 OEI61147.1 KOX01174.1 KPI26485.1 KPQ02829.1 OEN35083.1 KOX37867.1 KPL33203.1 KPV45380.1 OEN35408.1 KOX47623.1 KPM51038.1 KQB54807.1 OIX26336.1

Representative examples of putrescine aminotransferase (EC 2.6.1.82) are given below in Table 5 and identified by their EMBL/GenBank/DDBJ ID numbers. Any of the bacteria given in Table 10 can be engineered with any version of the putrescine aminotransferase (EC 2.6.1.82) set forth in Table 3 and Table 5. For instance, the bacteria can be engineered with a version of the putrescine aminotransferase enzyme that has at least 50% nucleotide similarity with any of the versions of putrescine aminotransferase given in Table 5 (e.g., at least nucleotide 60% similarity, at least 70% nucleotide similarity, at least 80% nucleotide similarity, at least 90% nucleotide similarity, at least 91% nucleotide similarity, at least 92% nucleotide similarity, at least 93% nucleotide similarity, at least 94% nucleotide similarity, at least 95% nucleotide similarity, at least 96% nucleotide similarity, at least 97% nucleotide similarity, at least 98% nucleotide similarity, at least 99% nucleotide similarity, at least 99.5% nucleotide similarity, at least 99.9% nucleotide similarity, or 100% nucleotide similarity).

TABLE 5 Representative Examples of Putrescine Aminotransferase by EMBL/GenBank/DDBJ ID Number AAA57874.1 ACB17060.1 AEJ58471.1 AID92376.1 AAA89152.1 ACF64513.1 AEN66465.1 AII63595.1 AAC36832.1 ACF70070.1 AEQ14325.1 AIP96878.1 AAC45301.1 ACF88918.1 AEW04404.1 AIR04884.1 AAC74384.1 ACH48710.1 AEW63332.1 AIR60611.1 AAC75709.1 ACH77510.1 AEW75317.1 AIR68505.1 AAC76108.3 ACI09453.1 AEX02383.1 AIS03494.1 AAFI0980.1 ACI18235.1 AFC33584.1 AIS53235.1 AAG03522.1 ACI36066.1 AFG42020.1 AIT00514.1 AAG03688.1 ACI77901.1 AFH65907.1 AIU72158.1 AAG58206.1 ACI77902.1 AFI89823.1 AIW78685.1 AAKI5486.1 ACI77903.1 AFJ30752.1 AIW86257.1 AAL22091.1 ACI77904.1 AFJ45596.1 AIX66695.1 AAN44587.2 ACI77905.1 AFJ57021.1 AIZ84136.1 AAN82273.1 ACN47379.1 AFM41617.1 AJA28077.1 AAO70680.1 ACO02631.1 AFM61662.1 AJB64485.1 AAP18399.1 ACO80985.1 AFN34266.1 AJC52685.1 AAV78920.1 ACR65342.1 AFR02837.1 AJC61854.1 AAX67071.1 ACS85106.1 AFS72647.1 AJC65876.1 AAZ89792.1 ACT07527.1 AFT85698.1 AJE19840.1 ABA89323.1 ACT12462.1 AFU12013.1 AJE57644.1 ABB67447.1 ACT27738.1 AGB76663.1 AJE82594.1 ABE08957.1 ACX87602.1 AGF56701.1 AJF57894.1 ABF05173.1 ACY90298.1 AGH86154.1 AJF75010.1 ABG71145.1 ACZ77451.1 AGM28805.1 AJH17424.1 ABJ02583.1 ADA75444.1 AGN85841.1 AJK49269.1 ABJ15261.1 ADD58285.1 AGQ74484.1 AJ086687.1 ABO88369.1 ADF63987.1 AGR60480.1 AJQ98395.1 ABP62186.1 ADM97796.1 AHA09869.1 AJY76773.1 ABR78896.1 ADO46913.1 AHA67171.1 AJZ91824.1 ABU78707.1 ADO70560.1 AHA67172.1 AKE62036.1 ABV07484.1 ADR28470.1 AHB72039.1 AKE93437.1 ABV15541.1 ADT76707.1 AHE60723.1 AKH08854.1 ABV20592.1 ADX19008.1 AHE69148.1 AKH23767.1 ABX24187.1 AEA71912.1 AHF76631.1 AKK34697.1 ABX64022.1 AEE58362.1 AHJ76496.2 AKK40619.1 ABX69344.1 AEE97629.1 AHM77480.1 AKK49917.1 ABX75605.1 AEG95705.1 AHM83064.1 AKL15453.1 ABY42524.1 AEI06121.1 AHN81979.1 AKL34316.1 ACA76303.1 AEI45944.1 AHY10460.1 AKL96946.1 ACB04157.1 AEJ41147.1 AHY72510.1 AKM18742.1 AKM36624.1 BAG78878.1 CCF65898.1 CEG33484.1 AKP48388.1 BAI27353.1 CCI78933.1 CEH27897.1 AKP75846.1 BAI32529.1 CCJ45694.1 CEH28958.1 AKZ54414.1 BAI37675.1 CCJ72687.1 CEJ63776.1 ALA75381.1 BAK33480.1 CCJ77939.1 CEK06962.1 ALB43935.1 BAM00748.1 CCJ80840.1 CEL88139.1 ALB53581.1 BAN45963.1 CCJ87365.1 CEO89736.1 ALB68770.1 BAN57107.1 CCJ91133.1 CEP33002.1 ALB72871.1 BAS27610.1 CCK00585.1 CFW77176.1 ALC72125.1 BAS27927.1 CCK05055.1 CJF89882.1 ALD27706.1 BAT36548.1 CCK09612.1 CKG89699.1 ALK33515.1 BAT40862.1 CCK25971.1 CNQ38822.1 ALL90941.1 BAT45090.1 CCK48380.1 CNT85510.1 ALO12800.1 BAU25986.1 CCO07408.1 CNU20511.1 ALO15071.1 BAU53092.1 CCO08483.1 CNU75336.1 ALR25918.1 CAB99164.1 CCY61522.1 CPR21341.1 ALR78149.1 CAD07742.1 CDB46597.1 CPR52929.1 ALX80070.1 CAD55516.1 CDC39173.1 CPR70581.1 ALY14616.1 CAG74449.1 CDD12313.1 CPS20475.1 ALZ69902.1 CAJ90253.1 CDK69254.1 CPU47210.1 AMA74351.1 CAQ90518.1 CDK78180.1 CPU50448.1 AMJ41057.1 CAR00034.1 CDL09266.1 CPU63604.1 AMJ69166.1 CAR04699.1 CDL16320.1 CPV69500.1 AMKII196.1 CAR09890.2 CDL21785.1 CPW19061.1 AMW45996.1 CAR14711.1 CDL24460.1 CPW19086.1 AMX16618.1 CAR19687.1 CDL41008.1 CPW42553.1 ANK35521.1 CAR34636.1 CDL43466.1 CQA01107.1 ANM83865.1 CAR38915.1 CDL49947.1 CQA05377.1 ANO24137.1 CAR61129.1 CDL54548.1 CQR59780.1 ANO91000.1 CAS10914.1 CDL60105.1 CQR65737.1 ANP19910.1 CAU99632.1 CDN08464.1 CQR76108.1 ANZ85526.1 CBA27530.1 CDN83823.1 CRF31866.1 AOM43730.1 CBG36194.1 CDO12367.1 CRK82822.1 APA44613.1 CBG91495.1 CDQ16366.1 CRL90015.1 BAA14871.1 CBH75900.1 CDQ55161.1 CSL03976.1 BAA16525.1 CBI02339.1 CDS92449.1 CSN57331.1 BAA94599.1 CBI02439.1 CDU33631.1 CSP97983.1 BAA94600.1 CBJ02843.1 CDU41038.1 CSS48268.1 BAB37378.1 CBL20779.1 CDW60669.1 CST07703.1 BAD88710.1 CBW19289.1 CDZ85955.1 CTQ00194.1 BAE77123.1 CCC31907.1 CDZ90589.1 CTQ01408.1 CTQ06965.1 EDY59830.2 EFL03670.1 EHC45475.1 CTQ10470.1 EEH12859.1 EFL18682.1 EHC45503.1 CTQ20562.1 EEI19352.1 EFL30368.1 EHC52082.1 CTQ78696.1 EEI70764.1 EFL33839.1 EHC52087.1 CTR79713.1 EEI93920.1 EFL36249.1 EHC52088.1 CTR96904.1 EEK74306.1 EFO59858.1 EHC61796.1 CTS73379.1 EEL07176.1 EFP71978.1 EHC61797.1 CTS73419.1 EEL35424.1 EFP71979.1 EHC67244.1 CTT28505.1 EEL41357.1 EFR14711.1 EHC67259.1 CTT56172.1 EEL47872.1 EFU36955.1 EHC75056.1 CTT69475.1 EEL58542.1 EFV42072.1 EHC75092.1 CTU79150.1 EEL71807.1 EFW49740.1 EHC81432.1 CTU88023.1 EEL84498.1 EFW54280.1 EHC81436.1 CTU94690.1 EEM06318.1 EFW57755.1 EHC81453.1 CTV09894.1 EEM17585.1 EGB14251.1 EHC82194.1 CTV11053.1 EEP53384.1 EGB62034.1 EHC82200.1 CTX20702.1 EEP61904.1 EGB65436.1 EHC87537.1 CTZ29307.1 EEQ93121.1 EGB73934.1 EHC87548.1 CTZ49322.1 EEW41109.1 EGB87427.1 EHC99340.1 CUI62304.1 EFC54109.1 EGC96496.1 EHC99346.1 CUJ87125.1 EFE05843.1 EGE35595.1 EHC99347.1 CUKI9452.1 EFE61929.2 EGH58156.1 EHC99662.1 CUV19889.1 EFF04850.2 EGI09466.1 EHC99665.1 CUV29759.1 EFF11713.2 EGI14765.1 EHC99666.1 CUV44247.1 EF188372.1 EGI20132.1 EHD22256.1 CUW27398.1 EFJ64643.1 EGI39453.1 EHJ00584.1 CUX83295.1 EFJ70989.1 EGI44536.1 EHJ80884.1 CVKI6600.1 EFJ81337.1 EGI49547.1 EHJ80892.1 EAU62914.1 EFJ85921.1 EGI91691.1 EHM38093.1 EDL55484.1 EFJ98691.1 EGI91882.1 EHM49393.1 EDO56632.1 EFK04657.1 EGI91908.1 EHP66038.1 EDQ32965.1 EFK09659.1 EGJ05807.1 EHT11055.1 EDS93910.1 EFKI3604.1 EGKI8274.1 EHU06080.1 EDU66756.1 EFK21010.1 EGK35042.1 EHU06383.1 EDU92373.1 EFK23876.1 EGK57964.1 EHU09521.1 EDX36107.1 EFK46876.1 EGU98422.1 EHU19477.1 EDX43683.1 EFK49689.1 EHB43515.1 EHU22647.1 EDX70173.1 EFK57463.1 EHC32088.1 EHU26084.1 EDY23644.1 EFK70624.1 EHC32777.1 EHU36390.1 EDY55948.1 EFK75383.1 EHC32780.1 EHU39097.1 EDY58150.2 EFK91732.1 EHC32793.1 EHU51516.1 EHV54826.1 EJS52655.1 ENA37997.1 EPF23810.1 EHY68818.1 EJS66726.1 ENA43345.1 EPF68941.1 EID63416.1 EJS74470.1 ENC89529.1 EPH43618.1 EID68002.1 EJU35674.1 END51354.1 EPI71152.1 EIG80589.1 EJV59704.1 END88908.1 EPI71726.1 EIG93735.1 EJV88337.1 ENG94980.1 EPI91450.1 EIH10970.1 EJZ63610.1 ENH00344.1 EPI98428.1 EIH24433.1 EKB48854.1 ENH06977.1 EPI99620.1 EIH45756.1 EKI50350.1 ENZ36084.1 EPJ05539.1 EIH76113.1 EKN69369.1 ENZ85363.1 EPJ10674.1 EII21076.1 EKY15805.1 EOB13036.1 EQD48086.1 EII37121.1 ELC14392.1 EOO15443.1 EQN24196.1 EII44330.1 ELC16479.1 EOO21808.1 EQN91238.1 EIK73551.1 ELC36432.1 EOO40793.1 EQO58637.1 EIL52772.1 ELC95414.1 EOO75774.1 EQP45856.1 EIQ05705.1 ELD97045.1 EOO78537.1 EQQ02030.1 EIQ18685.1 ELE40056.1 EOP16122.1 EQV89459.1 EIQ33923.1 ELE53047.1 EOP27458.1 EQX26002.1 EIQ57498.1 ELE57708.1 EOP41686.1 EQX85393.1 EIQ69925.1 ELG86056.1 EOP56689.1 EQY15934.1 EIQ70386.1 ELI22530.1 EOP57538.1 EQY57475.1 EJE66457.1 ELJ68100.1 EOP72097.1 EQZ98152.1 EJE84374.1 ELK42117.1 EOP74673.1 ERI03907.1 EJF29639.1 ELS58123.1 EOQ14051.1 ERI09683.1 EJK89144.1 ELV07387.1 EOQ45898.1 ERI93353.1 EJL13039.1 ELW30847.1 EOQ51737.1 ERK29115.1 EJL42219.1 EMD08043.1 EOU48296.1 ERO58336.1 EJP95200.1 EMR53712.1 EOU64078.1 ERO59766.1 EJQ09156.1 EMT38915.1 EOU77605.1 ERP00368.1 EJQ42479.1 EMT53291.1 EOU89114.1 ESA64895.1 EJQ53619.1 EMU59120.1 EOV03214.1 ESA65448.1 EJQ73265.1 EMU68070.1 EOV47394.1 ESA65917.1 EJQ76215.1 EMV17890.1 EOV55537.1 ESA75128.1 EJR03070.1 EMW94343.1 EOV76073.1 ESA87456.1 EJR30137.1 EMX18799.1 EOV93686.1 ESA87933.1 EJR37137.1 EMX29635.1 EOW03648.1 ESB01012.1 EJR56655.1 EMX36855.1 EOW19479.1 ESC94775.1 EJR60363.1 EMX47016.1 EOW29746.1 ESD11433.1 EJS01188.1 EMX83385.1 EOW62005.1 ESD19507.1 EJS10133.1 EMZ13604.1 EOW94128.1 ESD37227.1 EJS12547.1 ENA04805.1 EPF20607.1 ESD63043.1 E5D69311.1 EZD30976.1 KEJ44729.1 KFX06880.1 ESD77797.1 EZE08113.1 KEJ58710.1 KFX14235.1 ESE00825.1 EZE58040.1 KEJ72834.1 KFX74939.1 ESE81665.1 EII36257.1 KEL69605.1 KGA35360.1 ESE84032.1 EII49055.1 KEN52983.1 KGA42964.1 ESF53913.1 EII70721.1 KEN65251.1 KGF09343.1 ESG67336.1 EII83281.1 KEN97872.1 KGM62239.1 ESJ20736.1 EZK20097.1 KEO07702.1 KGM72003.1 ESKI5909.1 EZP34120.1 KEO29548.1 KGM83624.1 ESK33462.1 EZP69273.1 KEO37679.1 KGM85554.1 ESL70275.1 GAB53792.1 KER50700.1 KGT96644.1 ESM13806.1 GAD66768.1 KER78502.1 KHD16675.1 ESN17365.1 GAF37976.1 KEY61249.1 KHG17857.1 ESN64633.1 GAK71556.1 KEY61542.1 KHG23880.1 ESS57289.1 GAL45775.1 KEY61632.1 KHG24026.1 ESS68083.1 GAL51546.1 KEY61720.1 KHG25621.1 EST52466.1 GAL57703.1 KEY62070.1 KHI36730.1 ESU79725.1 GAM01523.1 KEY62211.1 KHJ14566.1 ESU79726.1 GAP71067.1 KEY62248.1 KHN51965.1 ETA87938.1 GAQ24599.1 KEY62600.1 KHN62432.1 ETC31011.1 GAQ52594.1 KEY62750.1 KHN91314.1 ETD63590.1 GAQ62824.1 KEY62777.1 KHO61939.1 ETE17194.1 GAR76344.1 KEY63154.1 KHS46174.1 ETE48332.1 GAS78753.1 KEY63197.1 KHS75073.1 ET191426.1 KCZ71192.1 KEY63491.1 KHT32808.1 ETJ22905.1 KDA56524.1 KEY63621.1 KHT39972.1 ETJ36492.1 KDE35397.1 KEY63666.1 KID02664.2 ETT76699.1 KDF12097.1 KEZ84112.1 KIH05031.1 ETY41938.1 KDF12267.1 KEZ91498.1 KIL36988.1 EUA69680.1 KDG92710.1 KFB98795.1 KIL37280.1 EUA84046.1 KDM54636.1 KFC77618.1 KIL75881.1 EWG73522.1 KDN97932.1 KFC87779.1 KIL78121.1 EWG77224.1 KDU32581.1 KFC92200.1 KIQ46533.1 EWS95005.1 KDV36696.1 KFC94055.1 KIQ55575.1 EWS95811.1 KDV41290.1 KFD40864.1 KIS45828.1 EYD83647.1 KDV63554.1 KFD77810.1 KIU31395.1 EYE21343.1 KDW29512.1 KFF72766.1 KIV76534.1 EYV13884.1 KDX22072.1 KFI56278.1 KJC02074.1 EYV14671.1 KDX46941.1 KFI63760.1 KJC05752.1 EYZ94185.1 KEA53701.1 KFI64199.1 KJC10953.1 EZA39087.1 KEF36300.1 KFI81170.1 KJF38320.1 KJH07563.1 KMK12937.1 KPO54643.1 KSB60709.1 KJM39013.1 KML66598.1 KPP86588.1 KSB77569.1 KJM95208.1 KMM34304.1 KPP90487.1 KST26609.1 KJN23016.1 KMM41841.1 KPQ06635.1 KST80109.1 KJS00574.1 KMN46751.1 KPQ07802.1 KSU03228.1 KJS11246.1 KMN64361.1 KPQ17574.1 KSU11825.1 KJS12052.1 KMN93720.1 KPQ18521.1 KSU28121.1 KJS23079.1 KMO70017.1 KPQ21853.1 KSX62841.1 KJS48202.1 KMO73567.1 KPQ48969.1 KSX94554.1 KJW31626.1 KMO79473.1 KPR56433.1 KSY24943.1 KJW48653.1 KMV34687.1 KPU43824.1 KSZ14257.1 KJX12962.1 KMV71410.1 KPW09941.1 KTH73029.1 KJX35546.1 KMY52755.1 KPW15746.1 KTI23444.1 KJZ82908.1 KMY52867.1 KPW54438.1 KTK26313.1 KJZ83822.1 KNA43034.1 KPW91211.1 KTK78251.1 KKA53732.1 KNB70753.1 KPX42861.1 KTM84786.1 KKB33451.1 KNB70796.1 KPX63485.1 KTO49964.1 KKB37484.1 KNC12151.1 KPY30896.1 KTO73181.1 KKC61647.1 KNC91419.1 KPY55802.1 KTP65662.1 KKI48768.1 KNF71262.1 KPY81707.1 KTZ06525.1 KKI89815.1 KNF81324.1 KPY97724.1 KUB34136.1 KKJ26361.1 KNH23702.1 KQB77808.1 KUE74614.1 KKK45477.1 KNN86024.1 KQC84343.1 KUH45954.1 KKM10135.1 KNW78813.1 KQJ43040.1 KUH57572.1 KKY41353.1 KNY77855.1 KQL34770.1 KUO48919.1 KKY86484.1 KNZ99940.1 KQL45807.1 KUQ85390.1 KLQ22117.1 KOA27411.1 KQL49683.1 KWU61736.1 KLT72735.1 KON69897.1 KQU20541.1 KWU68561.1 KLU65949.1 KON90844.1 KQU25399.1 KWW11355.1 KLV42517.1 KON96751.1 KRD84748.1 KXG99471.1 KLV56190.1 KOP04345.1 KRE10236.1 KXH99505.1 KLV64988.1 KOP73204.1 KRF52830.1 KXL57621.1 KLV65484.1 KOP92853.1 KRF58868.1 KXQ38659.1 KLV74220.1 KOR79514.1 KRF60614.1 KYR51641.1 KLW86671.1 KOR86809.1 KRF63503.1 KYS98061.1 KLX58084.1 KPA87633.1 KRK41016.1 KYV66420.1 KLX94977.1 KPA87634.1 KRM06091.1 KZJ62467.1 KLY12232.1 KPB72987.1 KRM11195.1 OAC42867.1 KLY33021.1 KPL77404.1 KRQ86107.1 OAJ90061.1 KME67644.1 KPO05706.1 KRT40898.1 OAO74321.1 KMI32966.1 KPO33063.1 KSB12379.1 OCL20194.1 OCS62224.1 OEH16092.1 SAE79353.1 OCV69030.1 OEN36946.1 SBL80466.1 ODH23946.1 OFD09909.1 SBZ09436.1

Representative examples of gamma-aminobutyraldehyde dehydrogenase (EC 1.2.1.19) are given below in Table 6 and identified by their EMBL/GENBANK/DDBJ ID numbers. Any of the bacteria given in Table 10 can be engineered with any version of the gamma-aminobutyraldehyde dehydrogenase (EC 1.2.1.19) set forth in Table 3 and Table 6. For instance, the bacteria can be engineered with a version of the gamma-aminobutyraldehyde dehydrogenase enzyme that has at least 50% nucleotide similarity with any of the versions of gamma-aminobutyraldehyde dehydrogenase given in Table 6 (e.g., at least nucleotide 60% similarity, at least 70% nucleotide similarity, at least 80% nucleotide similarity, at least 90% nucleotide similarity, at least 91% nucleotide similarity, at least 92% nucleotide similarity, at least 93% nucleotide similarity, at least 94% nucleotide similarity, at least 95% nucleotide similarity, at least 96% nucleotide similarity, at least 97% nucleotide similarity, at least 98% nucleotide similarity, at least 99% nucleotide similarity, at least 99.5% nucleotide similarity, at least 99.9% nucleotide similarity, or 100% nucleotide similarity).

TABLE 6 Representative Examples of Gamma-Aminobutyraldehyde Dehydrogenase by EMBL/GENBANK/DDBJ ID Number AAA23428.1 AAX65500.1 ABE07141.1 ABO56067.1 AAC74382.1 AAY35300.1 ABE33447.1 ABP60799.1 AAC74526.1 AAY91615.1 ABE35009.1 ABP83011.1 AAG56331.1 AAZ88386.1 ABE58543.1 ABQ62162.1 AAL20515.1 ABA73866.1 ABF03934.1 ABQ79255.1 AAN43345.1 ABA76670.1 ABF07563.1 ABQ81306.1 AAN54343.1 ABA77271.1 ABF08506.1 ABR77355.1 AAN68409.1 ABA81134.1 ABF77276.1 ABR80823.1 AAN80331.1 ABB06719.1 ABG69453.1 ABU77182.1 AAO69141.1 ABB09933.1 ABI88593.1 ABV05856.1 AAP17225.1 ABB61850.1 ABI91617.1 ABV12611.1 AAV77220.1 ABC35115.1 ABJ00886.1 ABV19407.1 ABV19711.1 ADF61409.1 AFG40645.1 AGO56529.1 ABV42738.1 ADF61777.1 AFI68614.1 AGO56534.1 ABV94754.1 ADI12862.1 AFI89822.1 AGP45636.1 ABX21278.1 ADJ47943.1 AFJ28854.1 AGP48796.1 ABX67082.1 ADM97795.1 AFJ28952.1 AGP52381.1 ACA77853.1 ADN75355.1 AFJ47105.1 AGP54692.1 ACB02660.1 ADO48635.1 AFK56420.1 AGP54697.1 ACB16069.1 ADP16410.1 AFK67163.1 AGP60625.1 ACB17411.1 ADR26852.1 AFL53103.1 AGQ73200.1 ACD08717.1 ADT74882.1 AFM59735.1 AGR58814.1 ACF65188.1 ADT75049.1 AFM60144.1 AGS23468.1 ACH48735.1 ADV53576.1 AFN32345.1 AGS72121.1 ACI07089.1 ADX17297.1 AFO48697.1 AGZ34904.1 ACI11169.1 AEC17673.1 AFO86070.1 AGZ34909.1 ACI11654.1 AEE56233.1 AFO92872.1 AGZ36730.1 ACI38546.1 AEE56444.1 AFR02836.1 AHA65135.1 ACI83776.1 AEG95612.1 AFR27692.1 AHA65444.1 ACI83777.1 AEG98095.1 AFR30100.1 AHA65445.1 ACI83778.1 AEG98933.1 AFR31023.1 AHB59062.1 ACI83779.1 AEH78268.1 AFS74542.1 AHB70534.1 ACI83780.1 AEH79912.1 AFS74651.1 AHB70670.1 ACI84176.1 AEI77057.1 AFT90302.1 AHC33991.1 ACI84177.1 AEI81569.1 AFT90471.1 AHC33996.1 ACI84178.1 AEJ11708.1 AFY18239.1 AHC38640.1 ACI84179.1 AEJ41144.1 AFY18244.1 AHC86568.1 ACI84180.1 AEJ56308.1 AGB72506.1 AHC90526.1 ACI98856.1 AEJ56491.1 AGB72704.1 AHC99932.1 ACL96708.1 AEK44843.1 AGB74580.1 AHD03574.1 ACN46267.1 AEN65037.1 AGB75454.1 AHD13184.1 ACR63729.1 AEQ12441.1 AGB78252.1 AHD17058.1 ACS85105.1 AEV61105.1 AGE94564.1 AHE51105.1 ACT07528.1 AEW60590.1 AGG75097.1 AHE57975.1 ACT12461.1 AEW61596.1 AGI23954.1 AHE58040.1 ACX87601.1 AEW61597.1 AGI25578.1 AHE70444.1 ACY88405.1 AEW73833.1 AGK03386.1 AHF76632.1 ACZ77452.1 AEW96833.1 AGM29868.1 AHF85737.1 ACZ84797.1 AEX05106.1 AGN78797.1 AHG19057.1 ACZ84868.1 AEX05672.1 AGN78800.1 AHG19062.1 ADA74159.1 AEX21381.1 AGN79081.1 AHG38795.1 ADD56229.1 AEY02655.1 AGN81120.1 AHH95453.1 ADD56381.1 AFG40539.1 AGN84096.1 AHH96134.1 AHI31496.1 AIO83941.1 AKA25271.1 ANM82203.1 AHI73863.1 AIP25746.1 AKA26423.1 ANP17955.1 AHK28152.1 AIP94956.1 AKA26428.1 ANZ87342.1 AHK28260.1 AIR03200.1 AKA26652.1 AOM46387.1 AHK29047.1 AIR62232.1 AKC39739.1 AOM69814.1 AHK29048.1 AIR68506.1 AKE96156.1 AOT33034.1 AHK29235.1 AIS00809.1 AKF49081.1 APA42536.1 AHK29423.1 AIS00819.1 AKG67805.1 APA42696.1 AHK34315.1 AIT03707.1 AKG67810.1 BAA14869.1 AHL32427.1 AIU71844.1 AKH07208.1 BAA15073.1 AHM79287.1 AIU71849.1 AKH08765.1 BAB35471.1 AHM80280.1 AIW48087.1 AKH26598.1 BAD88708.1 AHM84957.1 AIW76907.1 AKH26766.1 BAG42223.1 AHM85917.1 AIX63251.1 AKH85122.1 BAG77050.1 AHN80401.1 AIZ82499.1 AKJ10458.1 BAI25150.1 AHW62955.1 AJA14625.1 AKJ98810.1 BAI25318.1 AHX59431.1 AJA25872.1 AKK26535.1 BAI30293.1 AHY13380.1 AJC55682.1 AKK48033.1 BAI30398.1 AHY70456.1 AJC65875.1 AKK48134.1 BAI35600.1 AHZ69437.1 AJC81199.1 AKL12092.1 BAI35738.1 AHZ75601.1 AJD42887.1 AKL36390.1 BAL95971.1 AHZ75934.1 AJE42771.1 AKM34859.1 BAN47691.1 AIA06216.1 AJE55657.1 AKM34956.1 BAN47978.1 AIC18252.1 AJE55826.1 AKM45294.1 BAN50325.1 AIC18257.1 AJE81228.1 AKN71659.1 BAN50330.1 AIC29053.1 AJF56173.1 AKR56664.1 BAN56084.1 AID34200.1 AJF56280.1 AKR58199.1 CAC47084.1 AID90110.1 AJF67554.1 AKS06052.1 CAD01728.1 AIG78005.1 AJF67987.1 AKS06057.1 CAG74448.1 AIG79529.1 AJF73013.1 ALD25372.1 CAQ89037.1 AII03300.1 AJG15382.1 ALL90586.1 CAQ98298.1 AII05641.1 AJK47164.1 ALQ29888.1 CAR02855.1 AII06622.1 AIO83449.1 ALR27562.1 CAR07796.2 AII07903.1 AJP04064.1 ALY13061.1 CAR12812.1 AII88152.1 AJQ48790.1 ALY13176.1 CAR12894.1 AII13059.1 AJQ89920.1 ALZ65876.1 CAR17782.1 AII13068.1 AJT64083.1 ALZ66856.1 CAR37392.1 AIL63307.1 AJX74179.1 AMW41259.1 CAR50912.1 AIN56881.1 AJY44820.1 AMW41352.1 CAS09132.1 AIN58220.1 AJZ89630.1 AMX15658.1 CAU97432.1 AIO70590.1 AKA21608.1 ANK32128.1 CAZ86962.1 CBA30725.1 CDG17619.1 CDX35494.1 CTQ00586.1 CBG87141.1 CDH77402.1 CDX39763.1 CTQ03890.1 CBG88353.1 CDK71151.1 CDX50647.1 CTQ10217.1 CBJ00907.1 CDK74582.1 CDX52898.1 CTQ15467.1 CBJ01019.1 CDL26553.1 CDX53624.1 CTQ16305.1 CBW17622.1 CDL56081.1 CDX58882.1 CTQ16977.1 CCB65972.1 CDL81552.1 CDX59913.1 CTQ17997.1 CCB67003.1 CDL81886.1 CDX61300.1 CTQ25284.1 CCB67169.1 CDM87455.1 CDX61327.1 CTR39889.1 CCC30509.1 CDN05905.1 CDX61366.1 CTS37133.1 CCE10783.1 CDN06835.1 CDX62732.1 CTS49511.1 CCF61531.1 CDN82002.1 CDZ83389.1 CTS54984.1 CCH28399.1 CDO06723.1 CEG54345.1 CTT37563.1 CCH31748.1 CDO11198.1 CEI20766.1 CTT55391.1 CCH72874.1 CDO20175.1 CEJ64257.1 CTT62054.1 CCH76962.1 CDO27859.1 CEL27766.1 CTT65179.1 CCH77412.1 CDP84626.1 CEL27771.1 CTT92436.1 CCH79600.1 CDQ13701.1 CEL84834.1 CTT92613.1 CCI52108.1 CDQ14695.1 CEL86039.1 CTT97100.1 CCI77183.1 CDR01601.1 CEP29887.1 CTU01835.1 CCJ43834.1 CDR17539.1 CFU00610.1 CTU36153.1 CCJ43945.1 CDU36030.1 CPR21343.1 CTU72845.1 CCJ80233.1 CDU38743.1 CQD06815.1 CTV40159.1 CCKO2487.1 CDW92927.1 CQR61483.1 CTV56108.1 CCK27139.1 CDX11539.1 CRI57441.1 CTV74457.1 CCK27147.1 CDX11561.1 CRI58732.1 CTW04360.1 CCK46650.1 CDX14815.1 CRL88003.1 CTW29476.1 CCM79078.1 CDX15464.1 CRP27791.1 CTW61879.1 CCM79926.1 CDX15608.1 CRQ48403.1 CTW77542.1 CCN44439.1 CDX15708.1 CRZ15796.1 CTX33307.1 CCQ17877.1 CDX18128.1 CSK40308.1 CTY24484.1 CCT59175.1 CDX23952.1 CSK40325.1 CTZ61796.1 CCV08313.1 CDX24321.1 CSL03164.1 CTZ76546.1 CCV10163.1 CDX24344.1 CSM54609.1 CTZ79234.1 CCV14388.1 CDX24795.1 CSM54649.1 CTZ96800.1 CCV15291.1 CDX26102.1 CSN55245.1 CUI28728.1 CCW32353.1 CDX30033.1 CSP80178.1 CUJ66815.1 CDF82476.1 CDX30137.1 CSP84594.1 CUJ82879.1 CDF82481.1 CDX32833.1 CSP99410.1 CUZ08279.1 CDF83258.1 CDX33250.1 CSS89574.1 EDM61330.1 CDG13595.1 CDX33780.1 CTP99211.1 EDS91265.1 ED592029.1 EFK52086.1 EGJ05085.1 EIC82100.1 EDU65292.1 EFK66278.1 EGJ74429.1 EID61817.1 EDU90202.1 EFK74995.1 EGK24148.1 EID62214.1 EDU90317.1 EFK91145.1 EGK24149.1 EID65440.1 EDX34020.1 EFL88470.1 EGK24615.1 EID65521.1 EDX35915.1 EFM58433.1 EGK24616.1 EID73534.1 EDX46872.1 EFO59324.1 EGK37820.1 EIE52002.1 EDY24930.1 EFP69095.1 EGK60394.1 EIF92872.1 EDY65642.1 EFP69402.1 EGO94631.1 EIG83929.1 EED35505.1 EFR14050.1 EGU95611.1 EIG94831.1 EED97074.1 EFU33457.1 EGW40786.1 EIH12409.1 EEE03881.1 EFV41685.1 EGX55949.1 EIH21939.1 EEE05415.1 EFV42196.1 EHB41733.1 EIH44123.1 EEP49475.1 EFV44308.1 EHD22257.1 EIH77056.1 EEP84228.1 EGB59482.1 EHH02231.1 EII23324.1 EET48351.1 EGB68820.1 EHH09516.1 EII32616.1 EET48956.1 EGB72004.1 EHH11988.1 EII44042.1 EEW39317.1 EGB90260.1 EHJ94704.1 EIK70381.1 EEW60473.1 EGB98679.1 EHJ94844.1 EIK70690.1 EEX16532.1 EGC95168.1 EHK52408.1 EIK97767.1 EFC56792.1 EGD06231.1 EHK54788.1 EIK97772.1 EFE08792.1 EGE34132.1 EHK66824.1 EIL50217.1 EFE63903.2 EGE48689.1 EHK74830.1 EIL50351.1 EFE64066.2 EGE61394.1 EHM27681.1 EIM73619.1 EFF07668.2 EGF89341.1 EHM47677.1 EIQ09709.1 EFF07812.2 EGG47793.1 EHN75593.1 EIQ75858.1 EFF12655.2 EGI10883.1 EHP43848.1 EJE59098.1 EFF12736.2 EGI11039.1 EHP62718.1 EJE61181.1 EFG35656.2 EGI17601.1 EHP64017.1 EJE85045.1 EFH33353.1 EGI21877.1 EHT05663.1 EJE96318.1 EFI90126.1 EGI22685.1 EHT13683.1 EJF29138.1 EFJ64881.1 EGI41263.1 EHU11201.1 EJF32265.1 EFJ72274.1 EGI41264.1 EHU13340.1 EJF68495.1 EFJ83495.1 EGI46454.1 EHU15614.1 EJF68500.1 EFJ89608.1 EGI47073.1 EHU24532.1 EJI90289.1 EFJ98868.1 EGI51604.1 EHU29232.1 EJI93345.1 EFK05124.1 EGI51699.1 EHU31012.1 EJI93407.1 EFKI5965.1 EGI96778.1 EHU41094.1 EJI95486.1 EFKI9444.1 EGI99670.1 EHU45943.1 EJI95544.1 EFK26532.1 EGI99749.1 EHU59778.1 EJI96663.1 EFK45262.1 EGJ03157.1 EHV59483.1 EJI98843.1 EJJ00315.1 ELC41369.1 ENA45932.1 EPE95228.1 EJJ07858.1 ELC41538.1 ENC92169.1 EPF16860.1 EJK91259.1 ELC88918.1 END53755.1 EPH43419.1 EJK91378.1 ELC89051.1 END93044.1 EPH43431.1 EJL01279.1 ELE01126.1 ENG98074.1 EPI73506.1 EJL02848.1 ELE01606.1 ENH03358.1 EPI73882.1 EJL08255.1 ELE44498.1 ENH09610.1 EPI87463.1 EJL08816.1 ELE44659.1 ENY73407.1 EPJ00727.1 EJL08880.1 ELE56019.1 ENY78290.1 EPJ01132.1 EJL16742.1 ELE56114.1 ENZ86937.1 EPJ03992.1 EJL17014.1 ELE60912.1 EOD53374.1 EPJ12747.1 EJO32261.1 ELE61186.1 EOQ49232.1 EPJ38971.1 EJT03922.1 ELG89411.1 EOQ49914.1 EPJ38980.1 EJU29480.1 ELG90335.1 EOQ61470.1 EPJ81214.1 EJZ04156.1 ELI30197.1 EOQ65631.1 EPJ81219.1 EJZ05782.1 ELI31157.1 EOU43508.1 EPJ89017.1 EJZ07520.1 ELJ74005.1 EOU43864.1 EPL05218.1 EJZ11850.1 ELQ84051.1 EOU68015.1 EPR07720.1 EJZ13633.1 ELQ90577.1 EOU70063.1 EQD81697.1 EJZ18209.1 ELV07386.1 EOU79907.1 EQD82324.1 EJZ22729.1 ELW35774.1 EOU81119.1 EQD83794.1 EJZ67420.1 ELX11035.1 EOU96152.1 EQD87767.1 EJZ67421.1 EMD12755.1 EOU96255.1 EQL44300.1 EKE69095.1 EMD12954.1 EOV09796.1 EQM34719.1 EKF44031.1 EMD13067.1 EOV10270.1 EQM69852.1 EKF58906.1 EMF25251.1 EOV49578.1 EQM71564.1 EKI53765.1 EMP54680.1 EOV63174.1 EQM71569.1 EKI53852.1 EMP54686.1 EOV63548.1 EQM75964.1 EKT77536.1 EMR54447.1 EOV79497.1 EQM77609.1 EKU47209.1 EMU62810.1 EOV79860.1 EQM78485.1 EKU47702.1 EMU70199.1 EOV87779.1 EQM79321.1 EKX82560.1 EMV21190.1 EOW08077.1 EQM80144.1 EKX83133.1 EMX05854.1 EOW08486.1 EQN28573.1 EKX83138.1 EMX21136.1 EOW21036.1 EQN28672.1 EKX85141.1 EMX32353.1 EOW21374.1 EQN99840.1 EKZ96977.1 EMX40913.1 EOW24870.1 EQN99841.1 EKZ99926.1 EMX51161.1 EOW26044.1 EQO00250.1 ELB93420.1 EMX88242.1 EOW65040.1 EQO68143.1 ELC09512.1 EMY35234.1 EOW98830.1 EQO71509.1 ELC09701.1 ENA08671.1 EPB97616.1 EQP56400.1 ELC19003.1 ENA40359.1 EPC03794.1 EQQ14012.1 EQQ14796.1 ESA95270.1 ESU76946.1 ESY68060.1 EQV92076.1 ESB01449.1 ESU81649.1 ESY74421.1 EQV93438.1 ESD02695.1 ESU81650.1 ESY80296.1 EQX28154.1 ESD09814.1 ESW36007.1 ESY83492.1 EQX88295.1 ESD21218.1 ESW41503.1 ESY84782.1 EQX88882.1 ESD33644.1 ESW64252.1 ESY90437.1 EQY25054.1 ESD67552.1 ESW66425.1 ESY93751.1 EQY25162.1 ESD75875.1 ESW68009.1 ESZ00304.1 EQY62629.1 ESD88637.1 ESW86999.1 ESZ01923.1 EQY63166.1 ESD99184.1 ESW87442.1 ESZ09540.1 EQZ93705.1 ESE82501.1 ESW90408.1 ESZ09896.1 ERA03230.1 ESE84822.1 ESW91937.1 ESZ13256.1 ERB51269.1 ESF48176.1 ESX01731.1 ESZ14738.1 ERE03382.1 ESG58184.1 ESX14872.1 ESZ24600.1 ERF62800.1 ESJ13234.1 ESX15364.1 ESZ25961.1 ERF79994.1 ESJ21013.1 ESX27250.1 ESZ27305.1 ERF80025.1 ESK09882.1 ESX43501.1 ESZ28042.1 ERF86678.1 ESK10485.1 ESX52337.1 ESZ34731.1 ERH52669.1 ESK37171.1 ESX56930.1 ESZ35713.1 ERH54945.1 ESK37414.1 ESX58061.1 ESZ39312.1 ERH56364.1 ESL81948.1 ESX60692.1 ESZ47365.1 ERH56369.1 ESL82348.1 ESX73443.1 ESZ49754.1 ERI50841.1 ESM14498.1 ESX77081.1 ESZ50191.1 ERI52992.1 ESN13440.1 ESX81416.1 ESZ51262.1 ERK06991.1 ESQ05398.1 ESX87236.1 ESZ60420.1 ERKI4296.1 ESQ76607.1 ESX88150.1 ESZ62981.1 ERK98773.1 ESQ77377.1 ESX88342.1 ESZ63558.1 ERK98876.1 ESQ81731.1 ESY00266.1 ESZ67001.1 ERL53130.1 ESQ83104.1 ESY04276.1 ESZ70861.1 ERO58335.1 ESQ91911.1 ESY06338.1 ESZ73525.1 ERO62836.1 ESQ93897.1 ESY12861.1 ESZ73952.1 ERO63658.1 ESQ98710.1 ESY17564.1 ESZ75665.1 ERP07702.1 ESS14987.1 ESY18933.1 ETA08782.1 ERP86472.1 ESS59788.1 ESY26034.1 ETA86576.1 ERS89090.1 EST30101.1 ESY28484.1 ETC29664.1 ERT55553.1 EST30107.1 ESY30944.1 ETD30716.1 ESA66810.1 EST33761.1 ESY33527.1 ETD31105.1 ESA77122.1 EST33892.1 ESY37324.1 ETD62961.1 ESA78274.1 EST36063.1 ESY52717.1 ETE19722.1 ESA83620.1 EST39150.1 ESY60955.1 ETE53115.1 ESA83744.1 ESU49379.1 ESY66683.1 ETF04172.1 ETF05232.1 EZE53557.1 KDN76233.1 KEZ76822.1 ETF07523.1 EZH78629.1 KDN83114.1 KFB89554.1 ETI61741.1 EZH78632.1 KDN83117.1 KFB89559.1 ETK22368.1 EZI29263.1 KDO01521.1 KFC10517.1 ETK22373.1 EZI29268.1 KDQ69796.1 KFC67945.1 ETK33993.1 EZJ43273.1 KDS87067.1 KFC70569.1 ETK35735.1 EZJ52521.1 KDU28283.1 KFC75085.1 ETM65117.1 EZJ77242.1 KDV34603.1 KFC81786.1 ETM65275.1 EZJ87004.1 KDV38010.1 KFC91913.1 ETM67859.1 EZK23644.1 KDV65222.1 KFC95867.1 ETM67864.1 EZP27312.1 KDW32558.1 KFC99397.1 ETM68681.1 EZP41476.1 KDX18550.1 KFD74218.1 ETY48139.1 EZP45031.1 KDX47161.1 KFE44941.1 ETY48243.1 EZP62483.1 KEA05640.1 KFE53051.1 ETZ11507.1 GAB53548.1 KEA51004.1 KFF88438.1 EUB74063.1 GAB56017.1 KEC74664.1 KFF88443.1 EUB83842.1 GAD63079.1 KEC77821.1 KFF99222.1 EWC42375.1 GAD63084.1 KEG39710.1 KFG67154.1 EWG76330.1 GAK29357.1 KEH13576.1 KFG73420.1 EWH00701.1 GAK29362.1 KEJ48744.1 KFG77433.1 EWM12655.1 GAL43981.1 KEJ63425.1 KFI29656.1 EXF91839.1 GAL48526.1 KEJ77549.1 KFK85449.1 EXF93299.1 GAL58082.1 KEJ95365.1 KFK97286.1 EXF94820.1 GAM50401.1 KEL69022.1 KFK97291.1 EXF94825.1 GAO07729.1 KEN57716.1 KFL25738.1 EXF96398.1 GAP56165.1 KEN70496.1 KFL29966.1 EXJ51305.1 GAP56166.1 KEO01987.1 KFL38046.1 EXL03099.1 GAP56167.1 KEO12714.1 KFN19465.1 EXU69106.1 KDA58453.1 KEO35027.1 KFN41111.1 EXU88516.1 KDD67292.1 KEO51439.1 KFN46900.1 EYC51688.1 KDD68894.1 KEO53693.1 KFN49964.1 EYD86031.1 KDD69165.1 KEO57514.1 KFN51535.1 EYR82110.1 KDD69170.1 KER68883.1 KFX06879.1 EYT83596.1 KDE38101.1 KES06595.1 KFX69867.1 EYU66295.1 KDE98698.1 KES20242.1 KGA35361.1 EYV04090.1 KDF06849.1 KES21942.1 KGA42963.1 EYV10968.1 KDF18076.1 KES22773.1 KGD59263.1 EZA00470.1 KDF20685.1 KES22778.1 KGD94090.1 EZA36281.1 KDG95704.1 KEX91709.1 KGE65706.1 EZD25558.1 KDG97056.1 KEX92394.1 KGE65711.1 EZD99900.1 KDM67929.1 KEY87097.1 KGF68263.1 KGF72312.1 KIC09090.1 KJF69984.1 KJZ40441.1 KGI67195.1 KIC40995.1 KJF70827.1 KJZ40446.1 KGI94899.1 KIC41133.1 KJH08553.1 KJZ45327.1 KGJ03236.1 KIC83744.1 KJH75518.1 KJZ45333.1 KGK24105.1 KIC99939.2 KJH75523.1 KJZ66226.1 KGM32302.1 KIC99947.1 KJH76614.1 KJZ66231.1 KGM44306.1 KID09632.1 KJH78831.1 KKA04889.1 KGM58952.1 KIF07001.1 KJH87663.1 KKA04894.1 KGM69324.1 KIF26716.1 KJH87668.1 KKA09911.1 KGM78828.1 KIF43517.1 KJK01996.1 KKA37777.1 KGM81944.1 KIF59716.1 KJK02001.1 KKA42030.1 KGP01633.1 KIF59721.1 KJK03668.1 KKA53217.1 KGQ21090.1 KIF67705.1 KJK05212.1 KKB78257.1 KGR84694.1 KIH01614.1 KJK08131.1 KKB82836.1 KGT96645.1 KIK89863.1 KJK20451.1 KKC63115.1 KGU84905.1 KIK89868.1 KJK37817.1 KKD05136.1 KGU85044.1 KIQ45546.1 KJK52206.1 KKD60858.1 KGW16883.1 KIQ47862.1 KJK58811.1 KKE99588.1 KHA75030.1 KIQ55257.1 KJL20365.1 KKF00080.1 KHA75035.1 KIQ59125.1 KJL23069.1 KKF03311.1 KHD08750.1 KIQ63814.1 KJL30351.1 KKI46974.1 KHD11829.1 KIU18518.1 KJL31602.1 KKI46979.1 KHI27478.1 KIU34636.1 KJL33666.1 KKJ25486.1 KHJ12630.1 KIU47422.1 KJL48804.1 KKO14271.1 KHK63949.1 KIU53338.1 KJM37801.1 KKW63834.1 KHK63954.1 KIU53341.1 KJM97308.1 KKX63769.1 KHL04063.1 KIX41539.1 KJN29799.1 KKX64098.1 KHL17238.1 KIX76475.1 KJQ55807.1 KKY43260.1 KHL18800.1 KIY37490.1 KJQ55948.1 KKY88574.1 KHL69724.1 KIY39817.1 KJW23607.1 KKZ17922.1 KHN51966.1 KIY42118.1 KJW25580.1 KKZ17927.1 KHN62433.1 KIY42676.1 KJW52220.1 KKZ88372.1 KHN91313.1 KIZ13851.1 KJX08981.1 KLI09733.1 KHO23301.1 KIZ24787.1 KJX38421.1 KLI88767.1 KHO27139.1 KJC00426.1 KJY22909.1 KLI99518.1 KHO65650.1 KJC06180.1 KJY33089.1 KLK91133.1 KHS48549.1 KJC11238.1 KJY33790.1 KLO51629.1 KHS48554.1 KJE36612.1 KJY43331.1 KLQ25311.1 KHS75072.1 KJE78198.1 KJZ10920.1 KLT72736.1 KHT32807.1 KJF18418.1 KJZ37958.1 KLU27310.1 KHT39971.1 KJF21349.1 KJZ37963.1 KLV08340.1 KLV50364.1 KND42278.1 KOV74373.1 KPQ21464.1 KLV67254.1 KNF62763.1 KOV87450.1 KPQ21534.1 KLV72352.1 KNF78118.1 KOX03723.1 KPQ21854.1 KLW92152.1 KNF82323.1 KOX05951.1 KPR53957.1 KLX61073.1 KNG95257.1 KOX35809.1 KPW26103.1 KLX97485.1 KNH18859.1 KOX51055.1 KPW26988.1 KLY16841.1 KNH37980.1 KOY03131.1 KPW67069.1 KLY40951.1 KNH43304.1 KOY03136.1 KPW74859.1 KME63607.1 KNN88316.1 KOY58167.1 KPY59757.1 KMI30519.1 KNW77292.1 KPA89964.1 KPY87595.1 KMK11631.1 KNY72567.1 KPA90118.1 KQJ17275.1 KML66599.1 KNZ31302.1 KPB70152.1 KQJ36447.1 KMM42844.1 KNZ82970.1 KPC25344.1 KQJ45372.1 KMM79980.1 KNZ97006.1 KPC62377.1 KSH07068.1 KMM79984.1 KOA33208.1 KPC63412.1 KST34997.1 KMM93815.1 KOF21370.1 KPC68317.1 KSY01459.1 KMN10712.1 KOG30324.1 KPC80506.1 KTH76882.1 KMN10715.1 KOG34758.1 KPC83739.1 KTZ11478.1 KMN35503.1 KOG38875.1 KPC92801.1 KUN93478.1 KMN66213.1 KOG44119.1 KPF46210.1 KUU42596.1 KMN83689.1 KOG60686.1 KPF61380.1 KWZ91965.1 KMO68456.1 KOG65984.1 KPG35216.1 KXG93510.1 KMO68855.1 KOG73930.1 KPG89320.1 KXH01990.1 KMO70407.1 KOG84617.1 KPG89325.1 KXI02527.1 KMO71981.1 KOP04486.1 KPG90595.1 KXL57426.1 KMO77030.1 KOP81781.1 KPG90600.1 KXL65443.1 KMO77166.1 KOT34360.1 KPG95593.1 KXQ40269.1 KMO78179.1 KOT54726.1 KPG96003.1 KYR44624.1 KMO83081.1 KOT89785.1 KPH06793.1 KYR46262.1 KMO84977.1 KOT93096.1 KPL32866.1 KYS89391.1 KMO98166.1 KOU23107.1 KPL68330.1 KYV69812.1 KMQ75593.1 KOU32059.1 KPN71959.1 KYV69919.1 KMS67055.1 KOU37064.1 KPN74360.1 KZJ61423.1 KMS84091.1 KOU48313.1 KPN92591.1 OAC44376.1 KMV13999.1 KOU68154.1 KPN92596.1 OAJ89643.1 KMV35767.1 KOU76809.1 KPO09259.1 OAJ89801.1 KNA39386.1 KOV10064.1 KPO42565.1 OAO73826.1 KNC09274.1 KOV34566.1 KPO48511.1 OCB47501.1 KNC93864.1 KOV38826.1 KPO53785.1 OCS64471.1 KND34924.1 KOV52198.1 KPP88272.1 OCS99847.1 KND39332.1 KOV66117.1 KPP99458.1 OCV46435.1 OCV69750.1 OEH12679.1 OEN32392.1 SAZ48890.1 ODH20373.1 OEH17081.1 OIR52348.1 SBX26203.1 ODN18141.1 OEI60939.1 OJF09290.1 OEG95421.1 OEN32142.1 SAD98048.1

Representative examples of arginine decarboxylase (EC 4.1.1.19) are given below in Table 7 and identified by their EMBL/GENBANK/DDBJ ID numbers. Any of the bacteria given in Table 10 can be engineered with any version of the arginine decarboxylase (EC 4.1.1.19) set forth in Table 3 and Table 7. For instance, the bacteria can be engineered with a version of the arginine decarboxylase enzyme that has at least 50% nucleotide similarity with any of the versions of arginine decarboxylase given in Table 7 (e.g., at least nucleotide 60% similarity, at least 70% nucleotide similarity, at least 80% nucleotide similarity, at least 90% nucleotide similarity, at least 91% nucleotide similarity, at least 92% nucleotide similarity, at least 93% nucleotide similarity, at least 94% nucleotide similarity, at least 95% nucleotide similarity, at least 96% nucleotide similarity, at least 97% nucleotide similarity, at least 98% nucleotide similarity, at least 99% nucleotide similarity, at least 99.5% nucleotide similarity, at least 99.9% nucleotide similarity, or 100% nucleotide similarity).

TABLE 7 Representative Examples of Arginine Decarboxylase by EMBL/GENBANK/DDBJ ID Number AAA23481.1 AAG08224.1 AAN83546.1 AAQ61700.1 AAA24646.1 AAG58069.1 AAO10730.2 AAR35910.1 AAA62686.1 AAK03466.1 AAO28012.1 AAS63667.1 AAA69105.1 AAK65018.1 AAO58271.1 AAS81619.1 AAA97017.1 AAK65019.2 AAO70551.1 AAS94900.1 AAC24937.1 AAL21961.1 AAO71667.1 AAT33294.1 AAC75975.1 AAL23120.1 AAO78500.1 AAT56175.1 AAC77078.2 AAM38760.1 AAP07133.1 AAU16546.1 AAD06541.1 AAM43099.1 AAP10882.1 AAU26114.1 AAD07486.1 AAM86863.1 AAP18235.1 AAU91686.1 AAF09826.1 AAN44412.1 AAP27896.1 AAV78788.1 AAF40905.1 AAN54922.1 AAP77830.1 AAV81611.1 AAF82957.1 AAN66194.1 AAP99095.1 AAV82053.1 AAF96713.1 AAN81972.1 AAQ60544.1 AAV93917.1 AAW73474.1 ABE57906.1 ABM69334.1 ABW26679.1 AAW87910.1 ABF05062.1 ABM71261.1 ABX07146.1 AAW90125.1 ABF09627.1 ABM74623.1 ABX07983.1 AAX66932.1 ABF46066.1 ABM79561.1 ABX24332.1 AAY39411.1 ABF85039.1 ABN07206.1 ABX48976.1 AAY50992.1 ABF88624.1 ABN61275.1 ABX69181.1 AAY96086.1 ABG12304.1 ABN69317.1 ABX73818.1 AAZ33811.1 ABG12881.1 ABO16671.1 ABY34333.1 AAZ58866.1 ABG19102.1 ABO23486.1 ABY96523.1 AAZ89679.1 ABG19453.1 ABO48608.1 ABZ76368.1 ABA21777.1 ABG42373.1 ABO50340.1 ACA11160.1 ABA23030.1 ABG50504.1 ABO90758.1 ACA16086.1 ABA48961.1 ABG50611.1 ABP62006.1 ACA35608.1 ABA57077.1 ABG58847.1 ABP75372.1 ACA67146.1 ABA72371.1 ABI38635.1 ABP78675.1 ACA75078.1 ABA89337.1 ABI42627.1 ABP83495.1 ACA86341.1 ABB10893.1 ABI46161.1 ABQ05833.1 ACA99796.1 ABB26344.1 ABI55429.1 ABQ19043.1 ACB15562.1 ABB27130.1 ABI60410.1 ABQ25189.1 ACB16864.1 ABB31146.1 ABI68665.1 ABQ76774.1 ACB59509.1 ABB35370.1 ABI71549.1 ABQ91208.1 ACB76743.1 ABB36243.1 ABJ02367.1 ABR39026.1 ACB91563.1 ABB37372.1 ABJ14223.1 ABR71752.1 ACC79266.1 ABB44410.1 ABJ88595.1 ABR78771.1 ACC84558.1 ABB49107.1 ABKI5308.1 ABR85787.1 ACD05477.1 ABB50154.1 ABK38605.1 ABR88619.1 ACD08093.1 ABB56739.1 ABK43242.1 ABS07904.1 ACD08437.1 ABB57067.1 ABK47857.1 ABS26167.1 ACD22470.1 ABB63148.1 ABK75092.1 ABS44765.1 ACD56878.1 ABB67557.1 ABK82178.1 ABS51948.1 ACD84161.1 ABB74343.1 ABK86821.1 ABU58554.1 ACD95391.1 ABC18380.1 ABL00211.1 ABU74620.1 ACE82746.1 ABC20552.1 ABL82864.1 ABU75700.1 ACF30404.1 ABC33051.1 ABL89457.1 ABV15373.1 ACF53467.1 ABC81667.1 ABM00169.1 ABV17227.1 ACF61369.1 ABC98358.1 ABM02703.1 ABV17863.1 ACF63192.1 ABD03703.1 ABM13722.1 ABV37216.1 ACF69056.1 ABD80860.1 ABM17621.1 ABV43068.1 ACF90655.1 ABE08775.1 ABM25203.1 ABV49674.1 ACG73211.1 ABE10119.1 ABM29533.1 ABV67224.1 ACH39919.1 ABE55560.1 ABM63175.1 ABV87800.1 ACH51462.1 ACH52106.1 ACO76955.1 ADE16426.1 ADP85550.1 ACH64501.1 ACP07734.1 ADE54552.1 ADP96036.1 ACH76229.1 ACQ68147.1 ADE68385.1 ADQ16388.1 ACH83424.1 ACQ92008.1 ADE82828.1 ADQ41297.1 ACI09897.1 ACQ95950.1 ADF38194.1 ADQ80979.1 ACI17330.1 ACR12004.2 ADF54509.1 ADR18999.1 ACI27705.1 ACR67553.1 ADF63801.1 ADR23218.1 ACI37609.1 ACR70511.1 ADG05247.1 ADR28298.1 ACI78401.1 ACS84361.1 ADG69601.1 ADR33896.1 ACI78402.1 ACT05390.1 ADG90777.1 ADT68877.1 ACI78403.1 ACT14721.1 ADG93622.1 ADT69825.1 ACI78404.1 ACT17369.1 ADH59926.1 ADT76573.1 ACI78405.1 ACT94637.1 ADH64946.1 ADT88845.1 ACJ08154.1 ACU04524.1 ADH85917.1 ADU23228.1 ACJ29742.1 ACU08698.1 ADI13223.1 ADU27690.1 ACJ78722.1 ACU63629.1 ADI31741.1 ADU41306.1 ACK47011.1 ACU90402.1 ADI35097.1 ADU61911.1 ACK63941.1 ACU93413.1 ADI63948.1 ADU65890.1 ACK65701.1 ACV26547.1 ADJ27548.1 ADU70509.1 ACK72412.1 ACV27755.1 ADJ64931.1 ADU80224.1 ACK80041.1 ACV29034.1 ADK13228.1 ADU81854.1 ACK89576.1 ACX84176.1 ADK82353.1 ADU83415.1 ACK93714.1 ACX89634.1 ADK95316.1 ADU84974.1 ACL08484.1 ACX98134.1 ADL08911.1 ADU91399.1 ACL10977.1 ACX99534.1 ADL25363.1 ADV04673.1 ACL24678.1 ACY12668.1 ADL33935.1 ADV26011.1 ACL46250.1 ACY40093.1 ADM42795.1 ADV42555.1 ACL48808.1 ACY48301.1 ADN00148.1 ADV46298.1 ACL65409.1 ACY53514.1 ADN01531.1 ADV49133.1 ACL74193.1 ACY85796.1 ADN09145.1 ADV54125.1 ACL75477.1 ACY90136.1 ADN13212.1 ADV64798.1 ACM20036.1 ACZ12309.1 ADN74820.1 ADV66885.1 ACM64074.1 ACZ78457.1 ADN80145.1 ADW14248.1 ACM92229.1 ADA75259.1 ADO02588.1 ADW16260.1 ACN13264.1 ADB16530.1 ADO07215.1 ADW22931.1 ACN47236.1 ADB41493.1 ADO10713.1 ADW75122.1 ACO16949.1 ADB95292.1 ADO30989.1 ADX18873.1 ACO18249.1 ADC70718.1 ADO47091.1 ADX68773.1 ACO45270.1 ADD58093.1 ADO50285.1 ADY13324.1 ACO74026.1 ADD69353.1 ADO71288.1 ADY25759.1 ACO74435.1 ADD78376.1 ADP11444.1 ADY29884.1 ADY33564.1 AEG13685.1 AEU09127.1 AFI84424.1 ADY37564.1 AEG34055.1 AEV15411.1 AFI92112.1 ADY51339.1 AEG95551.1 AEV30675.1 AFJ01340.1 ADY54539.1 AEH00504.1 AEV33398.1 AFJ07943.1 ADY57443.1 AEH34628.1 AEV37643.1 AFJ30621.1 ADY59760.1 AEH46105.1 AEV60701.1 AFJ45704.1 ADZ04173.1 AEH48741.1 AEV60704.1 AFJ58120.1 ADZ79550.1 AEI50098.1 AEV60707.1 AFJ81937.1 ADZ81772.1 AEI66195.1 AEV67344.1 AFJ90992.1 ADZ83276.1 AEI78192.1 AEV70467.1 AFK03753.1 ADZ90751.1 AEI99981.1 AEV98535.1 AFK51272.1 AEA21246.1 AEJ04159.1 AEW03722.1 AFK70099.1 AEA43924.1 AEJ11150.1 AEW50294.1 AFL54808.1 AEA66789.1 AEJ19738.1 AEW63140.1 AFL66748.1 AEA80789.1 AEJ58269.1 AEW75168.1 AFL68607.1 AEA82850.1 AEJ60865.1 AEW84926.1 AFL74612.1 AEB00023.2 AEK23616.1 AEX02268.1 AFL79082.1 AEB11372.1 AEK58300.1 AEX23688.1 AFL80326.1 AEB28348.1 AEK61259.1 AEX24950.1 AFL84801.1 AEB56841.1 AEL05345.1 AEX53406.1 AFL98027.1 AEB69458.1 AEL27626.1 AEY01954.1 AFM03193.1 AEB99114.1 AEM47745.1 AEY67109.1 AFM14860.1 AEC00221.1 AEM53114.1 AFA47332.1 AFM34600.1 AEC17309.1 AEM69221.1 AFA73970.1 AFM61484.1 AEE18245.1 AEN15598.1 AFC23734.1 AFN34158.1 AEE24780.1 AEN17163.1 AFC87564.1 AFO49567.1 AEE58171.1 AEN18717.1 AFD07122.1 AFP36739.1 AEE70651.1 AEN66325.1 AFD26775.1 AFR05095.1 AEE81155.1 AEN73395.1 AFD56867.1 AFR34769.1 AEE81156.1 AEO44056.1 AFE10378.1 AFS72870.1 AEE97250.1 AEP12819.1 AFE59771.1 AFS76505.1 AEF05606.1 AEP31437.1 AFF19873.1 AFS77190.1 AEF16136.1 AEP37160.1 AFG36749.1 AFS77221.1 AEF16227.1 AEP84802.1 AFG41864.1 AFS78772.1 AEF17164.1 AEP86444.1 AFH38314.1 AFT72428.1 AEF23959.1 AEQ14110.1 AFH68776.1 AFT76388.1 AEF90677.1 AEQ98316.1 AFH99689.1 AFT80129.1 AEF92944.1 AER31405.1 AFI02753.1 AFT97219.1 AEF93776.1 AER40829.1 AFI04761.1 AFU69082.1 AEF98646.1 AER54676.1 AFI06437.1 AFU98562.1 AEG11827.1 AET65493.1 AFI07649.1 AFV06009.1 AFV13045.1 AFZ25951.1 AGG70048.1 AHA90255.1 AFV75467.1 AFZ28979.1 AGG70049.1 AHB58530.1 AFW94965.1 AFZ29238.1 AGG90911.1 AHB69077.1 AFX90032.1 AFZ34486.1 AGH42699.1 AHB88451.1 AFX91360.1 AFZ35910.1 AGH79375.1 AHC15721.1 AFY00064.1 AFZ44576.1 AGH84838.1 AHC33269.1 AFY17769.1 AFZ45212.1 AGH96448.1 AHC86082.1 AFY19232.1 AFZ47363.1 AGH98733.1 AHD06174.1 AFY20072.1 AFZ47406.1 AGI26195.1 AHD12720.1 AFY29829.1 AFZ52083.1 AGK04961.1 AHE48922.1 AFY31564.1 AFZ53867.1 AGK18815.1 AHE59627.1 AFY33433.1 AFZ55178.1 AGL50812.1 AHE60910.1 AFY36612.1 AFZ56231.1 AGL70280.1 AHE67762.1 AFY38143.1 AFZ58381.1 AGL71083.1 AHE69334.1 AFY42927.1 AFZ68543.1 AGN36083.1 AHE94171.1 AFY43519.1 AGA32088.1 AGN77656.1 AHE99491.1 AFY49150.1 AGA64911.1 AGN85662.1 AHF02503.1 AFY53502.1 AGA71585.1 AGO56879.1 AHF12870.1 AFY58942.1 AGA78721.1 AGP45919.1 AHF14205.1 AFY60143.1 AGA87856.1 AGP60451.1 AHF64905.1 AFY62113.1 AGA91287.1 AGP79570.1 AHF69813.1 AFY66936.1 AGB27428.1 AGP99328.1 AHF75852.1 AFY67481.1 AGB76810.1 AGQ75011.1 AHF89946.1 AFY68642.1 AGB83896.1 AGQ75715.1 AHG19399.1 AFY69655.1 AGC44465.1 AGQ92959.1 AHG42876.1 AFY74051.1 AGC68230.1 AGR60292.1 AHG91184.1 AFY79174.1 AGC68780.1 AGR77271.1 AHI04766.1 AFY80035.1 AGC77086.1 AGS39310.1 AHJ12914.1 AFY81634.1 AGD97973.1 AGT10955.1 AHJ98606.1 AFY88446.1 AGE21541.1 AGT74287.1 AHK03030.1 AFY89952.1 AGE28840.1 AGU60604.1 AHK76683.1 AFY96160.1 AGE63314.1 AGW85841.1 AHK78070.1 AFZ00099.1 AGF46648.1 AGX41788.1 AHL31986.1 AFZ00140.1 AGF47390.1 AGX44838.1 AHL74294.1 AFZ04829.1 AGF48115.1 AGY58242.1 AHM04085.1 AFZ05210.1 AGF48812.1 AGY75546.1 AHM04146.1 AFZ13691.1 AGF58399.1 AGY76455.1 AHM55552.1 AFZ14945.1 AGF77157.1 AGY88583.1 AHM55591.1 AFZ19310.1 AGF98737.1 AGZ37216.1 AHM56089.1 AFZ19658.1 AGG02742.1 AHA67006.1 ARM57413.1 AFZ23331.1 AGG32139.1 AHA68178.1 AHM72257.1 AHM77671.1 AII14684.1 AIY42499.1 AJH06775.1 AHM83263.1 AII44730.1 AIY44410.1 AJH14965.1 AHN36471.1 AII46407.1 AIY64168.1 AJH21997.1 AHN42175.1 AII48194.1 AIY65959.1 AJH79563.1 AHN78631.1 AII53131.1 AIZ35463.1 AJI04447.1 AHN81853.1 AII07653.1 AIZ41262.1 AJI11123.1 AHW76536.1 AII37593.1 AIZ46633.1 AJI18133.1 AHX13501.1 AIK36959.1 AIZ64390.1 AJI20378.1 AHX15381.1 AIL47042.1 AIZ80755.1 AJI21783.1 AHX61830.1 AIL63848.1 AIZ83995.1 AJI51649.1 AHY10273.1 AIM36252.1 AJAI2982.1 AJI68839.1 AHY11503.1 AIN60343.1 AJA27933.1 AJI86574.1 AHY41739.1 AIO35913.1 AJA50204.1 AJJ47448.1 AHY57313.1 AIO46079.1 AJA51748.1 AJJ79421.1 AHY72294.1 AIO86595.1 AJC46830.1 AJJ80961.1 AHY73771.1 AIP97923.1 AJC63707.1 AJK45428.1 AHZ25697.1 AIP98185.1 AJC67765.1 AJK84596.1 AHZ27049.1 AIQ93098.1 AJC84641.1 AJO76357.1 AHZ69904.1 AIQ94087.1 AJC86256.1 AJO84926.1 AHZ75105.1 AIQ96154.1 AJC87691.1 AJO86233.1 AIA25262.1 AIR06030.1 AJC89173.1 AJQ25834.1 AIA55267.1 AIR59441.1 AJC90641.1 AJQ49239.1 AIA73814.1 AIR70547.1 AJC94047.1 AJQ86078.1 AIC09292.1 AIR78811.1 AJD01709.1 AJQ92951.1 AIC13270.1 AIR89334.1 AJD06276.1 AJQ96966.1 AIC17824.1 AIS17530.1 AJD49796.1 AJR02566.1 AID43715.1 AIS18369.1 AJD72328.1 AJR08104.1 AID92227.1 AIS51300.1 AJD90845.1 AJW64789.1 AIE59498.1 AIS52271.1 AJE04066.1 AJY49487.1 AIE72691.1 AIT00342.1 AJE22826.1 AJY68826.1 AIE73587.1 AIU71685.1 AJE57486.1 AJZ41720.1 AIE80613.1 AIU74296.1 AJE58684.1 AJZ91147.1 AIF46276.1 AIU75005.1 AJF05803.1 AKA26859.1 AIF53874.1 AIW15710.1 AJF57742.1 AKA35243.1 AIG00462.1 AIW78499.1 AJF57774.1 AKA84246.1 AIG04575.1 AIX49204.1 AJF58959.1 AKA84438.1 AIG24465.1 AIX64799.1 AJF74877.1 AKB79206.1 AIG27859.1 AIX64838.1 AJG15944.1 AKB84150.1 AIG32739.1 AIX66185.1 AJG20615.1 AKC79848.1 AIG34894.1 AIX72613.1 AJG76397.1 AKC82482.1 AIG39523.1 AIY05985.1 AJG96579.1 AKC86571.1 AKD03611.1 AKM36436.1 ANM84924.1 BAI37476.1 AKD24893.1 AKM38713.1 ANO92070.1 BAI80755.1 AKD38345.1 AKM39687.1 ANP19758.1 BAI92054.1 AKD58010.1 AKM41511.1 ANP20955.1 BAJ02496.1 AKE51966.1 AKM92041.1 AOE77376.1 BAJ55572.1 AKE61219.1 AKN25889.1 AOM43879.1 BAJ56452.1 AKE61764.1 AKN61444.1 AOM48592.1 BAJ57954.1 AKE62865.1 AKN68937.1 AOM71331.1 BAJ60069.1 AKE94625.1 AKO77003.1 AOM71367.1 BAK12516.1 AKF03665.1 AKO96332.1 AOM72743.1 BAK33766.1 AKF25158.1 AKP45430.1 AOT31396.1 BAK70627.1 AKF49695.1 AKP46702.1 AOT34840.1 BAK73092.1 AKF81025.1 AKP53234.1 AOZ73672.1 BAK76369.1 AKG68123.1 AKP75073.1 AOZ75058.1 BAK98463.1 AKH08725.1 AKP76339.1 APA40674.1 BAL81291.1 AKH09890.1 AKQ46065.1 BAA16587.1 BAL84001.1 AKH17278.1 AKQ54037.1 BAA18683.1 BAM04828.1 AKH20941.1 AKQ67372.1 BAB06359.1 BAM33479.1 AKH23616.1 AKS06605.1 BAB37237.1 BAM50284.1 AKH24763.1 ALD23720.1 BAB75100.1 BAM53453.1 AKH64396.1 ALD23755.1 BAC09359.1 BAM96903.1 AKH69186.1 ALD27245.1 BAC61513.1 BAM98361.1 AKI01113.1 ALL39775.1 BAC92011.1 BAM99840.1 AKI01416.1 ALL89048.1 BAC94750.1 BAN02878.1 AKJ05268.1 ALR26077.1 BAD46988.1 BAN50817.1 AKJ41195.1 ALV75857.1 BAD64942.1 BAN52492.1 AKJ53541.1 ALV77901.1 BAD71463.1 BAN70003.1 AKJ64714.1 ALY14442.1 BAD78700.1 BAO54359.1 AKJ94106.1 ALY15746.1 BAE75293.1 BAO98678.1 AKJ97406.1 ALZ68230.1 BAE77001.1 BAP18257.1 AKK00568.1 ALZ68795.1 BAE78119.1 BAP32992.1 AKK49722.1 AMC46980.1 BAF69929.1 BAP43154.1 AKK66313.1 AMJ69296.1 BAF72313.1 BAP57483.1 AKK71642.1 AMW42739.1 BAG04503.1 BAP58680.1 AKL10485.1 AMX13191.1 BAG78731.1 BAU72598.1 AKL34468.1 AMX14483.1 BAG83373.1 BAU76793.1 AKL93588.1 ANC21029.1 BAH39093.1 CAA41337.1 AKL93616.1 ANH43655.1 BAH44872.1 CAA65422.1 AKM01921.1 ANK33675.1 BAH46155.1 CAB13336.1 AKM17405.1 ANK34958.1 BAI27222.1 CAD02911.1 AKM18378.1 ANM83718.1 BAI32252.1 CAD09281.1 CAD16072.1 CAQ47743.1 CBJ89096.1 CCC31740.1 CAD73363.1 CAQ70346.1 CBJ90126.1 CCC32782.1 CAE08874.1 CAQ81008.1 CBK62911.1 CCC57896.1 CAE09688.1 CAQ83180.1 CBK67757.1 CCD40282.1 CAE16054.1 CAQ83413.1 CBK75517.1 CCE19088.1 CAE18504.1 CAQ90371.1 CBK76873.1 CCE19708.1 CAE22324.1 CAR04456.1 CBK79250.1 CCE25072.1 CAE31349.1 CAR05775.1 CBK89692.1 CCF69259.1 CAE40174.1 CAR09410.1 CBK93443.1 CCF81308.1 CAE40569.1 CAR10810.1 CBK95550.1 CCG18048.1 CAE78014.1 CAR14453.1 CBK97421.1 CCG19863.1 CAG45065.1 CAR15764.1 CBK98076.1 CCG39483.1 CAG76815.1 CAR19475.1 CBK99239.1 CCG45166.1 CAH05973.1 CAR20645.1 CBL02265.1 CCG53314.1 CAH14236.1 CAR38786.1 CBL06429.1 CCG86051.1 CAH20481.1 CAR39908.1 CBL06632.1 CCG93076.1 CAH22440.1 CAR42872.1 CBL08498.1 CCG93934.1 CAI86150.1 CAR44185.1 CBL11309.1 CCG98515.1 CAI87882.1 CAR54969.1 CBL17760.1 CCH32647.1 CAJ25769.1 CAS10739.1 CBL18279.1 CCH47920.1 CAJ48085.1 CAU99219.1 CBL18584.1 CCH56597.1 CAJ50298.1 CAV01446.1 CBL22837.1 CCH64504.1 CAJ67721.1 CAV18374.1 CBL25542.1 CCH66661.1 CAJ70455.1 CAX29520.1 CBL33751.1 CCH73037.1 CAJ94006.1 CAX61193.1 CBL33969.1 CCH92456.1 CAJ99421.1 CAY46894.1 CBL41416.1 CCH95671.1 CAK17500.1 CAY75592.1 CBL46386.1 CCH97887.1 CAK24815.1 CAZ96112.1 CBN55346.1 CCH98535.1 CAK29281.1 CBA07513.1 CBV43889.1 CCI02124.1 CAL13443.1 CBA14903.1 CBW19161.1 CCI02703.1 CAL17846.1 CBA19555.1 CBW20794.1 CCI05752.1 CAL19596.1 CBA33565.1 CBW26940.1 CCI08081.1 CAL34892.1 CBG39474.1 CBW74145.1 CCI12608.1 CAL43775.1 CBG91721.1 CBY25861.1 CCI13269.1 CAL68563.1 CBH20174.1 CBY83075.1 CCI17237.1 CAM09122.1 CBI42666.1 CCA53939.1 CCI21360.1 CAM10863.1 CBI66029.1 CCA57465.1 CCI26537.1 CAN92612.1 CBJ02631.1 CCB69668.1 CCI26557.1 CAO97871.1 CBJ10334.1 CCB80486.1 CCI27928.1 CAP44435.1 CBJ81373.1 CCB85396.1 CCI31841.1 CAP53422.1 CBJ82759.1 CCB88488.1 CCI35741.1 CCI36837.1 CCQ91054.1 CDH35045.1 CDR33456.1 CCI78870.1 CCQ92417.1 CDH79904.1 CDR89846.1 CCJ33001.1 CCQ95938.1 CDK72226.1 CDR91413.1 CCJ37191.1 CCU62281.1 CDK72598.1 CDS49197.1 CCJ45542.1 CCU62303.1 CDK73473.1 CDS55845.1 CCJ46772.1 CCW05309.1 CDL10509.1 CDS84399.1 CCJ48129.1 CCW08807.1 CDL10510.1 CDS84845.1 CCJ54509.1 CCW14223.1 CDL14319.1 CDS89935.1 CCJ71908.1 CCW18613.1 CDL23452.1 CDS90150.1 CCJ80969.1 CCW31446.1 CDL25124.1 CDT62112.1 CCJ86077.1 CCW32107.1 CDL25589.1 CDT66706.1 CCJ89761.1 CDF57172.1 CDL37867.1 CDU33290.1 CCJ99408.1 CDF57711.1 CDL39140.1 CDU33786.1 CCK02016.1 CDF63223.1 CDL46170.1 CDU40272.1 CCK08384.1 CDF80723.1 CDL58441.1 CDU41159.1 CCK48228.1 CDF86470.1 CDL62104.1 CDY74095.1 CCK49456.1 CDF92784.1 CDL78959.1 CDZ24843.1 CCK74876.1 CDF94833.1 CDL81271.1 CDZ77476.1 CCK76603.1 CDF95827.1 CDL85577.1 CDZ85766.1 CCK78280.1 CDG13951.1 CDL87375.1 CDZ95756.1 CCK88893.1 CDG17974.1 CDL90268.1 CEA06065.1 CCK89714.1 CDG18838.1 CDL90667.1 CEA15542.1 CCK96041.1 CDG20298.1 CDM04050.1 CED57568.1 CCK96850.1 CDG21576.1 CDM25489.1 CED79730.1 CCK99990.1 CDG29398.1 CDM39225.1 CEE01723.1 CCL00838.1 CDG34413.1 CDM40785.1 CEF27490.1 CCL21002.1 CDG41242.1 CDM61201.1 CEF30990.1 CCL24016.1 CDG57553.1 CDM66630.1 CEF31449.1 CCL28925.1 CDG92785.1 CDM69239.1 CEF32542.1 CCL31787.1 CDG93659.1 CDM89651.1 CEF33945.1 CCO04884.1 CDG98742.1 CDM91302.1 CEG51568.1 CCO08560.1 CDG98818.1 CDN08348.1 CEG53321.1 CCO12883.1 CDG99561.1 CDN19844.1 CEG53340.1 CCP12708.1 CDG99621.1 CDN43705.1 CEG55497.1 CCP13614.1 CDH04673.1 CDN75234.1 CEG60275.1 CCP17046.1 CDH05982.1 CDN83562.1 CEI12237.1 CCP18758.1 CDH19229.1 CDO12490.1 CEI20008.1 CCP24686.1 CDH21449.1 CDO59353.1 CEJ65415.1 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KGF43280.1 KGL29400.1 KGQ63142.1 KHL80012.1 KGF45725.1 KGL30461.1 KGR36637.1 KHL81128.1 KGF49777.1 KGL33804.1 KGR59419.1 KHL83404.1 KGF52178.1 KGL37280.1 KGT92074.1 KHL85844.1 KGF56050.1 KGL61019.1 KGT93839.1 KHL86355.1 KGF63655.1 KGL63589.1 KGT99163.1 KHL87974.1 KGF63738.1 KGM06101.1 KGU86824.1 KHL89471.1 KGF88277.1 KGM21402.1 KGY09804.1 KHL90211.1 KGF91126.1 KGM27648.1 KGY14273.1 KHM48729.1 KGF94746.1 KGM27861.1 KHA74142.1 KHM49647.1 KGF98813.1 KGM51253.1 KHD07149.1 KHM50824.1 KGG02043.1 KGM53981.1 KHD11120.1 KHM92424.1 KGG06694.1 KGM56140.1 KHD26207.1 KHN50316.1 KGG08515.1 KGM58508.1 KHD65185.1 KHN57161.1 KGG13342.1 KGM62446.1 KHE42876.1 KHN63730.1 KGG16902.1 KGM67544.1 KHE71266.1 KHN93577.1 KGG20690.1 KGM71413.1 KHF26633.1 KHO63712.1 KGG25301.1 KGM76900.1 KHF28513.1 KHO63713.1 KGI22183.1 KGM78995.1 KHF28514.1 KHO64416.1 KGI51761.1 KGM83357.1 KHF29887.1 KHS42892.1 KGI53124.1 KGM85011.1 KHF33712.1 KHS44852.1 KGI59215.1 KGN81341.1 KHF33713.1 KHS51059.1 KGI60343.1 KGO11905.1 KHF36661.1 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KIX48438.1 KJH88029.1 KID06608.2 KIO64044.1 KIY14042.1 KII39829.1 KID09915.1 KIO64828.1 KIY14047.1 KII74678.1 KID53399.1 KIO64880.1 KIY40969.1 KII86656.1 KID55412.1 KIO74024.1 KIZ15345.1 KII97023.1 KIE10977.1 KIO75181.1 KIZ36062.1 KJK09157.1 KIE41615.1 KIP20469.1 KIZ50625.1 KJK17930.1 KIE47462.1 KIP22393.1 KJC02191.1 KJK39268.1 KIE57848.1 KIP30082.1 KJC03662.1 KJL17379.1 KIF05806.1 KIP63626.1 KJC05650.1 KJL19924.1 KIF16862.1 KIP77624.1 KJC06414.1 KJL32283.1 KIF29318.1 KIP86694.1 KJC11070.1 KJL32721.1 KIF31064.1 KIP92292.1 KJD22009.1 KJL47944.1 KIF41875.1 KIP99462.1 KJD31599.1 KJM40294.1 KIF44860.1 KIQ14588.1 KJD36996.1 KJM94811.1 KIF47532.1 KIQ28277.1 KJE41320.1 KJN20030.1 KIF56410.1 KIQ33154.1 KJE51611.1 KJR24918.1 KIF65759.1 KIQ47084.1 KJE82239.1 KJS62014.1 KIG15607.1 KIQ47216.1 KJF92896.1 KJU76259.1 KIH01698.1 KIQ55660.1 KJF94545.1 KIV08099.1 KIH04248.1 KIQ56619.1 KJF95976.1 KJV28421.1 KIH77871.1 KIQ60207.1 KJF96788.1 KJV33512.1 KIE85503.1 KIQ79728.1 KJF97649.1 KJV50178.1 KII76310.1 KIQ93208.1 KJE99814.1 KJW32727.1 KIJ73823.1 KIQ93267.1 KJG15312.1 KJW37560.1 KIJ80520.1 KIQ96608.1 KJG17565.1 KJW52381.1 KIK87497.1 KIR02360.1 KJG26623.1 KJW52975.1 KIL06168.1 KIR20554.1 KJG26708.1 KJX12328.1 KIL10730.1 KIR21483.1 KJG34980.1 KJX37016.1 KIL19543.1 KIR22223.1 KJG38239.1 KJY36082.1 KIL44729.1 KIS42545.1 KJG40540.1 KJY40855.1 KIL47560.1 KIS78068.1 KJG52887.1 KJY40903.1 KIL50316.1 KIT53654.1 KJG53015.1 KJY81951.1 KIM02995.1 KIU32905.1 KJG53489.1 KJY87010.1 KIM08543.1 KIU53521.1 KJG56948.1 KJY91596.1 KIM08702.1 KIV63259.1 KJH06976.1 KJY96966.1 KJZ05971.1 KKP36843.1 KKZ99926.1 KLD20683.1 KJZ06664.1 KKP40578.1 KLA23800.1 KLD21311.1 KJZ14999.1 KKP72963.1 KLA25117.1 KLD25825.1 KJZ15059.1 KKP75581.1 KLA31027.1 KLD31524.1 KJZ18625.1 KKP88656.1 KLA31452.1 KLD34072.1 KJZ33665.1 KKP98423.1 KLA96304.1 KLD38665.1 KJZ36032.1 KKQ21504.1 KLA99369.1 KLD63515.1 KJZ46139.1 KKQ47851.1 KLB01232.1 KLD63554.1 KJZ47590.1 KKQ55697.1 KLB11267.1 KLD66193.1 KJZ49128.1 KKR39473.1 KLB14716.1 KLD71246.1 KJZ60809.1 KKR41999.1 KLB22478.1 KLD80177.1 KJZ64968.1 KKR62922.1 KLB23603.1 KLE01246.1 KJZ83739.1 KKR69783.1 KLB27709.1 KLE03460.1 KJZ85288.1 KKS05164.1 KLB31750.1 KLE09177.1 KKA06404.1 KKS12144.1 KLB41291.1 KLE26682.1 KKA09841.1 KKS23019.1 KLC01821.1 KLI68356.1 KKA50887.1 KKS72573.1 KLC03447.1 KLI99305.1 KKA53937.1 KKS83788.1 KLC04907.1 KLJ14455.1 KKB03410.1 KKT00885.1 KLC18880.1 KLN47468.1 KKC56343.1 KKT03015.1 KLC19575.1 KLN96569.1 KKC64605.1 KKT10692.1 KLC24598.1 KLQ26951.1 KKC65426.1 KKT19966.1 KLC34817.1 KLQ27291.1 KKC79309.1 KKT24904.1 KLC35928.1 KLS52971.1 KKD31624.1 KKU39856.1 KLC38727.1 KLT65350.1 KKD58709.1 KKU48195.1 KLC42228.1 KLT70448.1 KKD62046.1 KKU49767.1 KLC42317.1 KLT72986.1 KKE81684.1 KKU75779.1 KLC49000.1 KLU04484.1 KKF37789.1 KKU87068.1 KLC54631.1 KLU62082.1 KKI42107.1 KKW45691.1 KLC62972.1 KLU63827.1 KKI44372.1 KKW50514.1 KLC63061.1 KLU67158.1 KKI47461.1 KKX49557.1 KLC63907.1 KLU99121.1 KKI52239.1 KKX58062.1 KLC72357.1 KLV00218.1 KKJ26482.1 KKX63732.1 KLC80920.1 KLV01109.1 KKJ98306.1 KKX66458.1 KLC81056.1 KLV04650.1 KKK99989.1 KKY43327.1 KLC86009.1 KLV04732.1 KKO13447.1 KKY43878.1 KLC90423.1 KLV10775.1 KKO45109.1 KKY65107.1 KLC94053.1 KLV43183.1 KKO48310.1 KKY79845.1 KLC98220.1 KLV47021.1 KKO64897.1 KKZ13187.1 KLD01509.1 KLV65167.1 KKO88680.1 KKZ18899.1 KLD01730.1 KLV65610.1 KKP30172.1 KKZ98376.1 KLD13508.1 KLV87502.1 KLW86530.1 KMQ23559.1 KND59806.1 KNZ96652.1 KLX50943.1 KMQ62276.1 KNE03726.1 KNZ97917.1 KLX57834.1 KMQ65521.1 KNE05809.1 KOA18143.1 KLX90366.1 KMQ67933.1 KNE07439.1 KOA19093.1 KLX95655.1 KMQ72280.1 KNE07808.1 KOA27317.1 KLY12052.1 KMQ73391.1 KNE08827.1 KOA35716.1 KLY34066.1 KMQ80007.1 KNE10687.1 KOA70224.1 KME68569.1 KMS77340.1 KNE13318.1 KOB20841.1 KMI32840.1 KMS90246.1 KNE14112.1 KOC89710.1 KMJ44158.1 KMT22151.1 KNE16939.1 KOC93511.1 KMJ45198.1 KMT22950.1 KNE17736.1 KOE81619.1 KMJ53196.1 KMT55834.1 KNE24464.1 KOE86500.1 KMK12312.1 KMT66157.1 KNE76189.1 KOE98088.1 KMK12388.1 KMT67645.1 KNF09795.1 KOF02803.1 KMK65741.1 KMT68464.1 KNF09831.1 KOG62614.1 KML20789.1 KMU66082.1 KNF69262.1 KOH46400.1 KML20912.1 KMV32029.1 KNF70644.1 KOO07593.1 KML48083.1 KMV34547.1 KNF79445.1 KOO13952.1 KML65003.1 KMV67940.1 KNF81883.1 KOO59694.1 KMM17341.1 KMV68973.1 KNH02424.1 KOO65836.1 KMM40283.1 KMV72040.1 KNH10085.1 KOO83034.1 KMM44209.1 KMW72260.1 KNH14365.1 KOP01917.1 KMM74668.1 KMW73819.1 KNH26156.1 KOP04218.1 KMM79436.1 KMW79566.1 KNH46145.1 KOP26957.1 KMM83437.1 KMY85028.1 KNN84556.1 KOP33536.1 KMM87484.1 KMZ12404.1 KNN85899.1 KOP34817.1 KMM91807.1 KMZ45161.1 KNW70656.1 KOP36989.1 KMM98149.1 KMZ45733.1 KNW74427.1 KOP96620.1 KMN11315.1 KMZ47283.1 KNX43865.1 KOQ72056.1 KMN13443.1 KMZ48992.1 KNX46584.1 KOQ79259.1 KMN18851.1 KMZ49221.1 KNX47560.1 KOR18913.1 KMN35621.1 KNA43180.1 KNX49078.1 KOR38747.1 KMN52211.1 KNA60505.1 KNX80210.1 KOR43231.1 KMN58862.1 KNB61204.1 KNX94009.1 KOR44320.1 KMN64506.1 KNC06722.1 KNY27166.1 KOR71845.1 KMN81232.1 KNC12046.1 KNY27231.1 KOS05070.1 KMN92035.1 KNC16749.1 KNY29154.1 KOS31558.1 KMO78898.1 KNC68501.1 KNY73335.1 KOS31918.1 KMO80014.1 KNC94639.1 KNY78421.1 KOS33911.1 KMP13875.1 KND51979.1 KNZ84104.1 KOU24174.1 KMP92251.1 KND54388.1 KNZ85960.1 KOU67934.1 KOV81195.1 KPG99865.1 KPQ35007.1 KPX66339.1 KOV90464.1 KPH01642.1 KPQ40221.1 KPX73444.1 KOV92694.1 KPH13642.1 KPQ42687.1 KPX75665.1 KOX28823.1 KPH55638.1 KPR47334.1 KPX84858.1 KOX89259.1 KPH58606.1 KPR54754.1 KPX85936.1 KOY02434.1 KPH60167.1 KPR57621.1 KPX98179.1 KOY04397.1 KPI00128.1 KPU43059.1 KPY01178.1 KOY33063.1 KPI21829.1 KPU45374.1 KPY03822.1 KOY42334.1 KPI28804.1 KPU53302.1 KPY16964.1 KOY42343.1 KPL49155.1 KPU59624.1 KPY20911.1 KOY45863.1 KPL85176.1 KPV48774.1 KPY29392.1 KOY50204.1 KPL99048.1 KPW00046.1 KPY38577.1 KOY52585.1 KPM32213.1 KPW04292.1 KPY41782.1 KOY61140.1 KPM49141.1 KPW13659.1 KPY47144.1 KOY61821.1 KPM63679.1 KPW16726.1 KPY54488.1 KOY85392.1 KPM65064.1 KPW17184.1 KPY56327.1 KPA10472.1 KPM81369.1 KPW23692.1 KPY64080.1 KPA52388.1 KPM81389.1 KPW27562.1 KPY70158.1 KPA53393.1 KPM84874.1 KPW34805.1 KPY74009.1 KPA53642.1 KPM96730.1 KPW42050.1 KPY80616.1 KPA88888.1 KPN17561.1 KPW48373.1 KPY90395.1 KPA90439.1 KPN64870.1 KPW51442.1 KPY92798.1 KPA92636.1 KPN71852.1 KPW62237.1 KPY99398.1 KPB67773.1 KPN73933.1 KPW62967.1 KPZ05993.1 KPB69211.1 KPN76064.1 KPW66391.1 KPZ14794.1 KPB79158.1 KPN88872.1 KPW77493.1 KPZ14841.1 KPB81326.1 KPN90573.1 KPW79725.1 KPZ23429.1 KPC07003.1 KPN90601.1 KPW85370.1 KPZ24832.1 KPC14008.1 KPO18579.1 KPW97437.1 KPZ30414.1 KPC35485.1 KPO32516.1 KPX00575.1 KPZ42886.1 KPC49975.1 KPO36865.1 KPX06301.1 KPZ47275.1 KPC57075.1 KPO46576.1 KPX09224.1 KPZ49946.1 KPC99496.1 KPO56914.1 KPX14980.1 KPZ52051.1 KPD01309.1 KPP89788.1 KPX22033.1 KPZ54935.1 KPD03211.1 KPP99272.1 KPX30196.1 KPZ63333.1 KPD11155.1 KPQ04554.1 KPX31760.1 KPZ63441.1 KPD20872.1 KPQ14293.1 KPX38634.1 KPZ64594.1 KPD32893.1 KPQ25476.1 KPX43708.1 KPZ67736.1 KPE49813.1 KPQ26228.1 KPX44429.1 KPZ72598.1 KPG83065.1 KPQ27964.1 KPX56237.1 KPZ74870.1 KPG95064.1 KPQ28712.1 KPX65518.1 KQA98214.1 KQB40657.1 KUQ52564.1 KYS97775.1 OCS96129.1 KQB42336.1 KUR40671.1 KYV67950.1 OCV53558.1 KQB52498.1 KUU48152.1 KYV73707.1 OCV69154.1 KQB89823.1 KWS16060.1 KZD84079.1 OCW73841.1 KQB94067.1 KWS38521.1 KZD88271.1 OCX56897.1 KQJ13933.1 KWS79043.1 KZE54774.1 ODH24470.1 KQJ19480.1 KWV37200.1 KZJ50109.1 ODJ92889.1 KQJ38967.1 KWV39942.1 KZJ59532.1 ODN20234.1 KQJ46044.1 KWX82425.1 OAC39173.1 ODR86790.1 KRG50855.1 KWZ89005.1 OAC43114.1 OEB17588.1 KRV51537.1 KXA39294.1 OAE94114.1 OEC25471.1 KRV54923.1 KXG92416.1 OAH32121.1 OEH12480.1 KSG98439.1 KXG97350.1 OAI64384.1 OEH95894.1 KST27457.1 KXH00368.1 OAJ86653.1 OEI62511.1 KST30748.1 KXH98343.1 OAJ87922.1 OEI65537.1 KSX90037.1 KXI03206.1 OAN24058.1 OEN36599.1 KSX90873.1 KXL66971.1 OAO68286.1 OFJ25861.1 KSZ13905.1 KXQ41321.1 OAO72924.1 OIN26436.1 KTH73164.1 KXQ42780.1 OBS13167.1 OIN31202.1 KTI23271.1 KXY17951.1 OCL17286.1 SAD71382.1 KTM92464.1 KXY86957.1 OCQ74268.1 SAE32738.1 KTP62443.1 KYR44969.1 OCS74958.1 SAY76613.1 KUG62774.1 KYR45993.1 OCS76529.1 SBX90614.1 KUH45679.1 KYS91454.1 OCS95943.1 SBZ90867.1

Representative examples of agmatinase (EC 3.5.3.11) are given below in Table 8 and identified by their EMBL/GENBANK/DDBJ ID numbers. Any of the bacteria given in Table 10 can be engineered with any version of the agmatinase (EC 3.5.3.11) set forth in Table 3 and Table 8. For instance, the bacteria can be engineered with a version of the agmatinase enzyme that has at least 50% nucleotide similarity with any of the versions of agmatinase given in Table 8 (e.g., at least nucleotide 60% similarity, at least 70% nucleotide similarity, at least 80% nucleotide similarity, at least 90% nucleotide similarity, at least 91% nucleotide similarity, at least 92% nucleotide similarity, at least 93% nucleotide similarity, at least 94% nucleotide similarity, at least 95% nucleotide similarity, at least 96% nucleotide similarity, at least 97% nucleotide similarity, at least 98% nucleotide similarity, at least 99% nucleotide similarity, at least 99.5% nucleotide similarity, at least 99.9% nucleotide similarity, or 10000 nucleotide similarity).

TABLE 8 Representative Examples of Agmatinase by EMBL/GENBANK/DDBJ ID Number AAA24647.1 AAA69104.1 AAA83909.1 AAB98295.1 AAC75974.1 AAF40906.1 AAG58067.1 AAK40769.1 AAK42842.1 AAL21953.1 AAL51292.1 AAL52351.1 AAM30619.1 AAN44408.1 AAN67809.1 AAN81970.1 AAO70550.1 AAO90262.1 AAP12232.1 AAP18231.1 AAP29255.1 AAQ00893.1 AAQ58167.1 AAQ87313.1 AAQ87384.1 AAT34764.1 AAT57507.1 AAT63474.1 AAU15214.1 AAU45759.1 AAV44785.1 AAV46799.1 AAV78787.1 AAV93914.1 AAV95718.1 AAV95721.1 AAV97369.1 AAW87909.1 AAW90124.1 AAX66926.1 AAY90871.2 AAZ22133.1 AAZ24263.1 AAZ54096.1 AAZ58777.1 AAZ65050.1 AAZ69672.1 AAZ89678.1 ABA19753.1 ABA52140.1 ABA53789.1 ABA73200.1 ABA74317.1 ABA79070.1 ABA81349.1 ABB07975.1 ABB10482.1 ABB11261.1 ABB12898.1 ABB27188.1 ABB37375.1 ABB50840.1 ABB63153.1 ABB67558.1 ABC20115.1 ABC35193.1 ABC36254.1 ABC90370.1 ABC90927.1 ABC99063.1 ABD02701.1 ABD10232.1 ABD53194.1 ABD54884.1 ABD55257.1 ABD68100.1 ABD68348.1 ABE08773.1 ABE29546.1 ABE35008.1 ABE43955.1 ABE52778.1 ABE55558.1 ABE60184.1 ABE75327.1 ABF05058.1 ABF41119.1 ABF53436.1 ABF63671.1 ABF63672.1 ABF77979.1 ABF78588.1 ABG05817.1 ABG32253.1 ABG32638.1 ABG32639.1 ABG62558.1 ABG70915.1 ABG82607.1 ABG87141.1 ABI47535.1 ABI59683.1 AB160409.1 ABI67996.1 ABI89619.1 ABI90194.1 ABJ02365.1 ABK02249.1 ABK16419.1 ABK71425.1 ABK71845.1 ABK73126.1 ABK75016.1 ABK78003.1 ABK88044.1 ABL69259.1 ABL73176.1 ABL77915.1 ABL82726.1 ABL82883.1 ABL88073.1 ABL91072.1 ABL91501.1 ABL91972.1 ABL92277.1 ABM02702.1 ABM10897.1 ABM11012.1 ABM11652.1 ABM13827.1 ABM29529.1 ABM37937.1 ABM56124.1 ABM71179.1 ABM73084.1 ABM76715.1 ABM79681.1 ABM79929.1 ABM94848.1 ABM98665.2 ABN06601.1 ABN56898.1 ABN70230.1 ABN76664.1 ABN78567.1 ABN87189.1 ABN87725.1 ABN92921.1 ABN92962.1 ABO09043.1 ABO18500.1 ABO23488.1 ABO36121.1 ABO49035.1 ABO56523.1 ABO58149.1 ABP42590.1 ABP43281.1 ABP45780.1 ABP51374.1 ABP62005.1 ABP70012.1 ABP86798.1 ABP94673.1 ABP96350.1 ABQ18665.1 ABQ26532.1 ABQ31960.1 ABQ33008.1 ABQ60179.1 ABQ77546.1 ABQ79666.1 ABQ87081.1 ABQ91371.1 ABR78770.1 ABR81216.1 ABR81751.1 ABS77512.1 ABU75701.1 ABV07331.1 ABV15371.1 ABV21194.1 ABV43067.1 ABV51572.1 ABV67817.1 ABV93477.1 ABX09748.1 ABX69169.1 ABX74248.1 ABX81911.1 ABY21971.1 ACA38569.1 ACA76446.1 ACB04033.1 ACB18855.1 ACC84325.1 ACD06722.1 ACD24294.1 ACE90614.1 ACE91158.1 ACE94809.1 ACF30403.1 ACF61915.1 ACF67727.1 ACF91868.1 ACH50852.1 ACH63482.1 ACH77920.1 ACI10057.1 ACI11642.1 ACI18698.1 ACI35219.1 ACI78406.1 ACI78407.1 ACI78408.1 ACI78409.1 ACI78410.1 ACJ29740.1 ACK73593.1 ACM05018.1 ACM06157.1 ACN13261.1 ACN47228.1 ACO74132.1 ACP07733.1 ACP21851.1 ACP21922.1 ACP26294.1 ACP35785.1 ACP36686.1 ACR61943.1 ACR70510.1 ACS32933.1 ACS41939.1 ACS89313.1 ACU08695.1 ACV76715.1 ACV81107.1 ACY53515.1 ACY85795.1 ACY90127.1 ACZ87232.1 ADA75255.1 ADB74457.1 ADC90860.1 ADD45355.1 ADD58091.1 ADD78375.1 ADE04586.1 ADE37357.1 ADE39009.1 ADE40257.1 ADE40278.1 ADE67897.1 ADE69284.1 ADE72169.1 ADE85469.1 ADE86001.1 ADF37727.1 ADF39062.1 ADF41976.1 ADF63800.1 ADG91441.1 ADG91991.1 ADI14533.1 ADJ63231.1 ADK07910.1 ADL07911.1 ADL18546.1 ADL44534.1 ADM42794.1 ADN75943.1 ADO10712.1 ADO30990.1 ADO47092.1 ADP11446.1 ADP83855.1 ADQ66311.1 ADR28296.1 ADT68876.1 ADT70429.1 ADT76571.1 ADT96768.1 ADT97392.1 ADT99263.1 ADU52417.1 ADU70503.1 ADV49134.1 ADV64546.1 ADV66173.1 ADX18864.1 ADX72077.1 ADY13321.1 ADY27253.1 ADY29885.1 ADY33548.1 ADY55312.1 ADY72884.1 ADZ04172.1 ADZ08379.1 ADZ10562.1 ADZ27749.1 ADZ83109.1 ADZ91927.1 AEA33345.1 AEA45611.1 AEA47221.1 AEA80791.1 AEA80792.1 AEB08603.1 AEB10992.1 AEB12421.1 AEC00219.1 AEE58170.1 AEE96159.1 AEF17260.1 AEF54342.1 AEF88522.1 AEF93913.1 AEF93919.1 AEF95254.1 AEF97223.1 AEG03799.1 AEG05228.1 AEG14656.1 AEG17355.1 AEG33547.1 AEG44996.1 AEG44997.1 AEG95549.1 AEH00503.1 AEH06103.1 AEH08712.1 AEH11147.1 AEH22925.1 AEH36766.1 AEH48221.1 AEH49662.1 AEH50623.1 AEI14843.1 AEI94329.1 AEI94330.1 AEJ58268.1 AEK22524.1 AEK23614.1 AEK61616.1 AEK64195.1 AEM40724.1 AEM58024.1 AEM69220.1 AEN05459.1 AEN05763.1 AEN06930.1 AEN66324.1 AEP88702.1 AEQ14108.1 AER31406.1 AEV37646.1 AEV38161.1 AEV61529.1 AEV87262.1 AEV97888.1 AEW04403.1 AEW06905.1 AEW63139.1 AEW75167.1 AEX02267.1 AEX23687.1 AFA38334.1 AFA38752.1 AFA47334.1 AFC24160.1 AFD00687.1 AFG41863.1 AFI84427.1 AFJ01337.1 AFJ30619.1 AFJ45705.1 AFJ59747.1 AFJ63961.1 AFK19996.1 AFL51309.1 AFL51840.1 AFM19977.1 AFM61483.1 AFO87859.1 AFO87860.1 AFO91682.1 AFO91683.1 AFP37519.1 AFP39918.1 AFP40726.1 AFP40804.1 AFQ48622.1 AFQ49589.1 AFQ50194.1 AFQ51687.1 AFR09275.1 AFS72872.1 AFS77227.1 AFV11211.1 AFY19072.1 AFY19668.1 AFY21148.1 AFY36898.1 AFY39232.1 AFY40247.1 AFY66803.1 AFY87223.1 AFZ10381.1 AFZ31237.1 AFZ34586.1 AFZ37423.1 AFZ44104.1 AFZ47238.1 AFZ54331.1 AFZ55267.1 AGA67678.1 AGA72691.1 AGB21222.1 AGB76811.1 AGB83895.1 AGC68778.1 AGC77085.1 AGD97972.1 AGE22498.1 AGE23989.1 AGG04209.1 AGG32138.1 AGG73823.1 AGG75093.1 AGH87553.1 AGI26201.1 AGI47257.1 AGI68304.1 AGI68305.1 AGI72348.1 AGI72349.1 AGI84982.1 AGJ55062.1 AGJ58747.1 AGJ59299.1 AGK77294.1 AGN38302.1 AGO56878.1 AGP45918.1 AGQ74348.1 AGQ92958.1 AGR60291.1 AGR77854.1 AGS21412.1 AGS21940.1 AGS26045.1 AGS39313.1 AGT07309.1 AGT11108.1 AGX41862.1 AGY56862.1 AGZ34567.1 AHA67015.1 AHB69078.1 AHC15724.1 AHD07591.1 AHD07965.1 AHD07966.1 AHD09199.1 AHD09200.1 AHE60912.1 AHE69335.1 AHF69002.1 AHF73775.1 AHF75853.1 AHG19398.1 AHK01119.1 AHK03741.1 AHM05195.1 AHM05332.1 AHM57412.1 AHM77673.1 AHM83265.1 AHN81844.1 AHW76535.1 AHY10272.1 AHY72292.1 AHZ23375.1 AIA74065.1 AIC26759.1 AIC27350.1 AID41526.1 AID92226.1 AIE61595.1 AIE72946.1 AIE75743.1 AIE81817.1 AIF82761.1 AIF84264.1 AIF84945.1 AIG28743.1 AIG32998.1 AIG35154.1 AIG39783.1 AIG97525.1 AII87322.1 AII87324.1 AIJ07652.1 AIJ37317.1 AIK37348.1 AIK38502.1 AIM26660.1 AIM28333.1 AIO30916.1 AIO31498.1 AIO35681.1 AIO35975.1 AIO36489.1 AIO44724.1 AIO46049.1 AIO46224.1 AIO49720.1 AIO70072.1 AIO70112.1 AIO82805.1 AIO84618.1 AIP28881.1 AIP29149.1 AIP96985.1 AIQ96062.1 AIQ98336.1 AIR06031.1 AIR59440.1 AIS52428.1 AIU71687.1 AIW15709.1 AIW78498.1 AIX49199.1 AIX64797.1 AIX72614.1 AIY06411.1 AIY17255.1 AIY19826.2 AIY19931.2 AIY44086.1 AIY47278.1 AIY65960.1 AIZ56989.1 AIZ83993.1 AJA15226.1 AJA27931.1 AJA92009.1 AJC63708.1 AJC78797.1 AJC79353.1 AJD40791.1 AJD44781.1 AJD44817.1 AJD52273.1 AJD92404.1 AJE47384.1 AJE57484.1 AJF57741.1 AJF74876.1 AJG14739.1 AJG17918.1 AJG79170.1 AJG94738.1 AJH06394.1 AJH17306.1 AJH80029.1 AJI07021.1 AJI11177.1 AJI18362.1 AJI19711.1 AJI21563.1 AJI23861.1 AJI24944.1 AJK42294.1 AJK48584.1 AJO84924.1 AJQ48197.1 AJW70766.1 AJX73400.1 AJX73637.1 AJY10662.1 AJY38564.1 AJY39189.1 AJY39634.1 AJY49045.1 AJY49192.1 AJY49305.1 AJZ58787.1 AJZ61461.1 AJZ62973.1 AJZ91146.1 AKA25996.1 AKA85572.1 AKB13293.1 AKB16072.1 AKB17277.1 AKB20676.1 AKB23916.1 AKB30046.1 AKB33946.1 AKB38310.1 AKB39394.1 AKB45534.1 AKB49003.1 AKB49561.1 AKB56266.1 AKB59739.1 AKB60366.1 AKB63578.1 AKB66937.1 AKB70291.1 AKB73823.1 AKB76958.1 AKB83790.1 AKB84178.1 AKD38344.1 AKE61765.1 AKE63966.1 AKE65066.1 AKE94626.1 AKG68119.1 AKG91930.1 AKH08717.1 AKH23614.1 AKH64397.1 AKH98312.1 AKH99850.1 AK101044.1 AKJ41197.1 AKJ64711.1 AKK49720.1 AKL10486.1 AKL34469.1 AKL94121.1 AKM00856.1 AKM03663.1 AKM20612.1 AKM36435.1 AKM38930.1 AKM44683.1 AKM92040.1 AKO77002.1 AKO96563.1 AKO98269.1 AKP48868.1 AKP80163.1 AKV73628.1 AKV75131.1 AKV75868.1 AKV77369.1 AKV78118.1 AKV79620.1 AKV80363.1 AKV81865.1 AKV82611.1 AKV84100.1 ALD23757.1 ALG82706.1 ALL39774.1 ALV77276.1 ALV81183.1 ALY14440.1 ALZ68232.1 AMJ69304.1 AMW42737.1 AMX08364.1 AMX14485.1 ANC16538.1 ANC22333.1 ANM83716.1 ANO90761.1 ANP19756.1 ANZ85663.1 AOM43881.1 AOM71329.1 AOT31398.1 APA40676.1 BAA16710.1 BAA17298.1 BAA80638.2 BAB07529.1 BAB37235.1 BAB51449.1 BAB65332.1 BAC14507.1 BAD63716.1 BAD66428.1 BAD77689.1 BAD85071.1 BAE75292.1 BAE77000.1 BAG30482.1 BAG45193.1 BAG46924.1 BAG78729.1 BAH31284.1 BAH46484.1 BAH50915.1 BAH51568.1 BAI27220.1 BAI32251.1 BAI37474.1 BAI75018.1 BAI75040.1 BAI75047.1 BAI80439.1 BAJ82447.1 BAK12515.1 BAK34589.1 BAK98432.1 BAK98465.1 BAL95958.1 BAN02875.1 BAN46237.1 BAN54991.1 BAN90497.1 BAU72144.1 BAU75360.1 BAU76701.1 CAB02517.1 CAB15776.1 CAC45820.1 CAC47080.1 CAD02910.1 CAD18729.1 CAD83324.1 CAD85058.1 CAE07927.1 CAE08937.1 CAE16053.1 CAE20145.1 CAE22388.1 CAE33200.1 CAE38071.1 CAE78008.1 CAE78232.1 CAF31141.1 CAH37930.1 CAH39062.1 CAI86151.1 CAI89357.1 CAJ10765.1 CAJ11914.1 CAJ35086.1 CAJ53446.1 CAJ67724.1 CAK07164.1 CAK09940.1 CAK10592.1 CAK16253.1 CAK16639.1 CAK24880.1 CAK29338.1 CAK29381.1 CAL44270.1 CAL68562.1 CAL80391.1 CAM05191.1 CAM09121.1 CAM10862.1 CAN90200.1 CAN99327.1 CAO97869.1 CAP14282.1 CAQ83181.1 CAQ90364.1 CAQ99884.1 CAR04454.1 CAR09553.2 CAR14451.1 CAR19473.1 CAR34499.1 CAR38778.1 CAR44182.1 CAR51520.1 CAR54274.1 CAR56347.1 CAR60989.1 CAS10737.1 CAU99217.1 CAV18375.1 CAX26528.1 CAX58939.1 CAX61192.1 CAY51214.1 CAY75590.1 CAZ86945.1 CAZ96113.1 CBA07510.1 CBA19557.1 CBA33563.1 CBG91722.1 CBH20171.1 CBI44700.1 CBJ02630.1 CBJ36000.1 CBJ41226.1 CBJ80582.1 CBJ89098.1 CBK43642.1 CBK64440.1 CBK76875.1 CBK99237.1 CBL02267.1 CBL06427.1 CBL17762.1 CBL18586.1 CBL22839.1 CBL25540.1 CBL28295.1 CBL41552.1 CBV41181.1 CBW19153.1 CCB64763.1 CCB65171.1 CCB70695.1 CCB85395.1 CCB88489.1 CCC19821.1 CCC31739.1 CCC41606.1 CCC82222.1 CCD03081.1 CCD03343.1 CCD89954.1 CCD93845.1 CCE01319.1 CCE10074.1 CCE15097.1 CCE17011.1 CCE95457.1 CCE96893.1 CCF18965.1 CCF20747.1 CCG46987.1 CCG52586.1 CCG86053.1 CCH00037.1 CCH71227.1 CCH91980.1 CCH94031.1 CCH97873.1 CCH98110.1 CCH99362.1 CCI04256.1 CCI06792.1 CCI07869.1 CCI14209.1 CCI14551.1 CCI18636.1 CCI20568.1 CCI26509.1 CCI27381.1 CCI27656.1 CCI29463.1 CCI33484.1 CCI33643.1 CCI38967.1 CCI52514.1 CCI78869.1 CCJ06579.1 CCJ36819.1 CCJ45540.1 CCJ49843.1 CCJ52441.1 CCJ71907.1 CCJ80970.1 CCJ86076.1 CCJ89760.1 CCJ99407.1 CCK02015.1 CCK08383.1 CCK48226.1 CCK74894.1 CCK78277.1 CCK89717.1 CCK96853.1 CCL00841.1 CCL21005.1 CCL28928.1 CCM75184.1 CCM77037.1 CCM78508.1 CCM79193.1 CCM80257.1 CCO04886.1 CCO05578.1 CCO05593.1 CCO06200.1 CCO08237.1 CCP10570.1 CCQ09657.1 CCQ10974.1 CCQ34449.1 CCQ35689.1 CCQ36200.1 CCQ47332.1 CCQ74550.1 CCQ94339.1 CCQ95023.1 CCQ95940.1 CCV06472.1 CCV13247.1 CCV63725.1 CCV65581.1 CCW06091.1 CCW16005.1 CCW31444.1 CDF80722.1 CDF85323.1 CDF86475.1 CDF92525.1 CDG13942.1 CDG18839.1 CDG20299.1 CDG31563.1 CDG92784.1 CDG98743.1 CDG99622.1 CDH05986.1 CDH21445.1 CDH24733.1 CDH33017.1 CDH74672.1 CDH78253.1 CDI05863.1 CDI08139.1 CDI40700.1 CDK71508.1 CDK72224.1 CDK72597.1 CDK98654.1 CDL10508.1 CDL11618.1 CDL16097.1 CDL17208.1 CDL19544.1 CDL23451.1 CDL25123.1 CDL39139.1 CDL46167.1 CDL57556.1 CDL57557.1 CDL58440.1 CDL62829.1 CDL63085.1 CDL79639.1 CDL85576.1 CDM42435.1 CDM57288.1 CDM60749.1 CDM60990.1 CDM66632.1 CDM91301.1 CDN08347.1 CDN42601.1 CDN83560.1 CDN91137.1 CDQ16187.1 CDR93058.1 CDS53731.1 CDS55128.1 CDS59015.1 CDS84404.1 CDS84851.1 CDT66748.1 CDU33788.1 CDU41160.1 CDW92944.1 CDX00216.1 CDX11223.1 CDX16126.1 CDX17209.1 CDX17653.1 CDX18157.1 CDX23096.1 CDX26808.1 CDX28868.1 CDX31490.1 CDX34075.1 CDX36972.1 CDX38569.1 CDX38670.1 CDX49350.1 CDX53768.1 CDX56980.1 CDX58275.1 CDX59705.1 CDX62547.1 CDY73639.1 CDY74077.1 CDY75840.1 CDY77024.1 CDY78583.1 CDZ23447.1 CDZ85765.1 CED57567.1 CEE01721.1 CEF30993.1 CEF31451.1 CEH98691.1 CE118991.1 CEI51711.1 CEJ65416.1 CEK22007.1 CEK37314.1 CEL88255.1 CEN33873.1 CEN34609.1 CEN35800.1 CEN39832.1 CEN43042.1 CEN51600.1 CEN51743.1 CEN53478.1 CEN53480.1 CEN53702.1 CEO41666.1 CEO90406.1 CEP33358.1 CEQ02613.1 CEY70465.1 CFC48269.1 CFT92190.1 CFT96567.1 CJA40003.1 CJC36758.1 CJF84864.1 CJG89416.1 CJI93354.1 CJI95124.1 CJN03702.1 CJN67826.1 COF22522.1 COF38764.1 COI45864.1 COP15970.1 COP30452.1 COP45895.1 COQ71690.1 CPR16225.1 CPR16252.1 CPR21886.1 CPR28567.1 CPR28568.1 CQR76249.1 CRF98508.1 CRH30681.1 CRH35397.1 CRH39702.1 CRH69483.1 CRI55920.1 CRI56443.1 CRL10051.1 CRL61080.1 CRL62208.1 CRL90920.1 CRL92325.1 CRP39759.1 CRP93373.1 CRQ49718.1 CRQ59532.1 CRV25744.1 CSB25877.1 CSB76203.1 CSC35023.1 CSI87493.1 CSK81664.1 CSN19142.1 CSP73809.1 CSS26770.1 CTQ00826.1 CTQ01842.1 CTQ07399.1 CTQ11021.1 CTQ21393.1 CTQ33005.1 CTQ42017.1 CTQ47453.1 CTQ50609.1 CTQ53954.1 CTQ63712.1 CTQ76095.1 CTR88335.1 CTS05166.1 CTS30798.1 CTT77634.1 CTT83409.1 CTT95037.1 CTU43832.1 CTU68877.1 CTV16782.1 CTV23427.1 CTV60644.1 CTW91398.1 CTZ55651.1 CTZ68789.1 CUB11509.1 CUB13588.1 CUB16299.1 CUB23833.1 CUB24713.1 CUB31352.1 CUB37524.1 CUB38342.1 CUB41881.1 CUB48656.1 CUB51818.1 CUB57702.1 CUH40798.1 CUH92888.1 CUJ17376.1 CUJ29157.1 CUJ95397.1 CVA34134.1 CVE90668.1 CVG47751.1 CZX11870.1 CZX80257.1 EAO57065.1 EAP72459.1 EAP93055.1 EAQ63147.1 EAQ97486.1 EAQ99338.2 EAR30280.1 EAR49722.1 EAR53967.1 EAR60303.1 EAS45732.1 EAS66652.1 EAT13839.1 EAU53062.1 EAW26172.1 EAW41481.1 EAY25698.1 EAY29686.1 EAY71091.1 EBA17342.1 EBA45829.1 EBA46625.1 EBA46696.1 EBA49948.1 EDK27088.1 EDK34419.1 EDL55746.1 EDL67758.1 EDM72574.1 EDM85436.1 EDN00141.1 EDN58209.1 EDN75782.1 EDO61990.1 EDO83906.1 EDO88009.1 EDP21555.1 EDP46398.1 EDP57830.1 EDP99239.1 EDQ32183.2 EDQ32422.2 EDQ33985.1 EDQ34081.2 EDS19662.1 EDS72096.1 EDS73897.1 EDS80988.1 EDS83158.1 EDS88464.1 EDS93649.1 EDT16696.1 EDT25032.1 EDT72172.1 EDU60242.1 EDU65565.1 EDU92236.1 EDW21378.1 EDX36044.1 EDX47360.1 EDX72527.1 EDY23983.1 EDY34967.1 EDY39135.1 EDY82527.1 EDZ41638.1 EDZ41715.1 EDZ42430.1 EDZ44891.1 EDZ45134.1 EDZ47076.1 EDZ51775.1 EDZ60731.1 EDZ60741.1 EEA81924.1 EEA96242.1 EEA96590.1 EEA96958.1 EEB32402.1 EEB44176.1 EEB65944.1 EEB71277.1 EEB71305.1 EEB77525.1 EEB78979.1 EEB83949.1 EEB85264.1 EEB85629.1 EEC31786.1 EEC32371.1 EED32136.1 EED33461.1 EED96977.1 EEE02117.1 EEE06332.1 EEE08690.1 EEE34962.1 EEE35534.1 EEE35828.1 EEE38756.1 EEE38911.1 EEE39080.1 EEE41906.1 EEE44992.1 EEE45349.1 EEE45625.1 EEE46631.1 EEF78555.1 EEG29984.1 EEG55452.1 EEG85448.1 EEH25515.1 EEH27429.1 EEI48479.1 EEK13686.1 EEK47650.1 EEN89060.1 EEO01852.1 EEO17496.1 EEP49793.1 EEP50112.1 EEP54377.1 EEP83565.1 EEQ48941.1 EES48642.1 EET02842.1 EET04446.1 EET46812.1 EET48304.1 EET48468.1 EEU96709.1 EEV88951.1 EEW39916.1 EEW41136.1 EEW57117.1 EEW57168.1 EEX09750.1 EEX09880.1 EEX09889.1 EEX10564.1 EEX10565.1 EEX13167.1 EEX13946.1 EEX22145.1 EEX36090.1 EEX49424.1 EEX69732.1 EEX74040.1 EEX77692.1 EEY45419.1 EEY72540.1 EEY99072.1 EEZ40965.1 EFB71687.1 EFB74416.1 EFB90964.1 EFC53923.1 EFC82450.1 EFC93346.1 EFD51996.1 EFE04795.2 EFE06568.1 EFE11218.1 EFE24314.1 EFE53195.1 EFE61787.2 EFE81272.2 EFE96243.1 EFF05370.2 EFF11560.2 EFF63745.1 EFF65458.1 EFF77651.1 EFG05259.1 EFG07008.1 EFG47867.1 EFG79255.1 EFG80390.1 EFH08237.1 EFH16891.1 EFI87351.1 EFJ68586.1 EFJ72104.1 EFJ78632.1 EFJ85217.1 EFJ95125.1 EFK02096.1 EFK07239.1 EFK16400.1 EFK22733.1 EFK27354.1 EFK33116.1 EFK43743.1 EFK52585.1 EFK66135.1 EFK73841.1 EFK92719.1 EFK93271.1 EFL53944.1 EFL89152.1 EFL90564.1 EFM05246.1 EFM19908.1 EFM24365.1 EFM59353.1 EFO29280.1 EFO29703.1 EFO59693.1 EFP56876.1 EFP71835.1 EFQ06576.1 EFQ61867.1 EFR18236.1 EFR40215.1 EFS98037.1 EFU36795.1 EFU68774.1 EFV39454.1 EFV63707.1 EFW12879.1 EFW30568.1 EFW49236.1 EFW57058.1 EFW59097.1 EGA66010.1 EGA71635.1 EGB61887.1 EGB66941.1 EGB73848.1 EGB86481.1 EGB97943.1 EGC01418.1 EGC01999.1 EGC96351.1 EGC98049.1 EGD34121.1 EGE35458.1 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EIK70683.1 EIK72394.1 EIK96204.1 EIL52555.1 EIM75905.1 EIQ05553.1 EIQ18545.1 EIQ26058.1 EIQ34462.1 EIQ57268.1 EIQ71651.1 EIQ78422.1 EIW91574.1 EJE70690.1 EJE72665.1 EJF28964.1 EJF37584.1 EJF40496.1 EJ191627.1 EJI91646.1 EJL04634.1 EJL08772.1 EJL13645.1 EJL86644.1 EJM95575.1 EJO22140.1 EJO55869.1 EJO56522.1 EJP30929.1 EJS87369.1 EJS88033.1 EJS88036.1 EJT07171.1 EJT86204.1 EJU28108.1 EJU32316.1 EJU32348.1 EJU33461.1 EJU35725.1 EJU55912.1 EJW18947.1 EJZ23180.1 EJZ23191.1 EJZ63478.1 EKB46124.1 EKB47998.1 EKE71933.1 EKF06697.1 EKF20235.1 EKF21363.1 EKF42800.1 EKF58465.1 EKI50661.1 EKJ96466.1 EKM19531.1 EKM27370.1 EKM33126.1 EKS07972.1 EKT55065.1 EKT55967.1 EKT65147.1 EKU51342.1 EKX63786.1 ELC14265.1 ELC16835.1 ELC37936.1 ELC95205.1 ELD97255.1 ELE41729.1 ELE53627.1 ELE58433.1 ELG86729.1 ELI22617.1 ELJ68846.1 ELP54032.1 ELP55275.1 ELP55913.1 ELP68231.1 ELQ87920.1 ELQ87969.1 ELQ88013.1 ELQ88771.1 ELQ91334.1 ELS26448.1 ELS26841.1 ELS27850.1 ELT47152.1 ELU52903.1 ELW31521.1 ELW85333.1 ELY27700.1 ELZ99543.1 EMD08742.1 EMI11336.1 EMI14266.1 EMP51369.1 EMR07851.1 EMS71620.1 EMS97913.1 EMT40199.1 EMU59685.1 EMU68325.1 EMV17924.1 EMW97460.1 EMX18620.1 EMX29475.1 EMX36709.1 EMX46863.1 EMX83205.1 ENA04653.1 ENA38209.1 ENA38530.1 ENA43836.1 ENC90022.1 END51199.1 END90131.1 ENG95642.1 ENH01174.1 ENH07605.1 ENY75730.1 ENZ85537.1 EOC16726.1 EOD01693.1 EOD42238.1 EON87502.1 EOQ46176.1 EOQ52661.1 EOR96368.1 EOU48067.1 EOU65286.1 EOU78385.1 EOU89739.1 EOV04148.1 EOV47238.1 EOV55387.1 EOV76750.1 EOV94389.1 EOW04340.1 EOW16261.1 EOW19941.1 EOW61850.1 EOW95130.1 EOZ98682.1 EPA97273.1 EPA99157.1 EPB97690.1 EPC14082.1 EPE98824.1 EPF13748.1 EPF18896.1 EPR26903.1 EPR73838.1 EPR73839.1 EPR76419.1 EPR76420.1 EPR77354.1 EPX76657.1 EPX79011.1 EPX79012.1 EPX79543.1 EPX80066.1 EPX81913.1 EPX81981.1 EPX84862.1 EPX85788.1 EPX87242.1 EPZ50642.1 EPZ55228.1 EQC48483.1 EQC49653.1 EQF26369.1 EQI88341.1 EQK40602.1 EQK42131.1 EQN24780.1 EQN91648.1 EQO59510.1 EQP47193.1 EQQ03969.1 EQV89274.1 EQX25771.1 EQX86240.1 EQY17582.1 EQY57338.1 EQZ99174.1 ERF77294.1 ERG11045.1 ERG42422.1 ERG53670.1 ERI00623.1 ERI28937.1 ERI30693.1 ERI31190.1 ERI32103.1 ERJ05871.1 ERJ12333.1 ERK11299.1 ERK12088.1 ERL54400.1 ERN41122.1 ERN42498.1 ERP09068.1 ERT09144.1 ERT14069.1 ESA61590.1 ESA67356.1 ESA68726.1 ESA72701.1 ESA84978.1 ESA92506.1 ESB01864.1 ESC99187.1 ESD05523.1 ESD21413.1 ESD37525.1 ESD70932.1 ESD76697.1 ESD90270.1 ESE04815.1 ESE83038.1 ESE86248.1 ESF53709.1 ESG73922.1 ESJ19424.1 ESK15534.1 ESK34333.1 ESL70090.1 ESM15735.1 ESN17179.1 ESQ21061.1 ESQ72660.1 ESR24857.1 EST58097.1 ESU79960.1 ESW56111.1 ETA01630.1 ETA52029.1 ETA68210.1 ETC31136.1 ETD59987.1 ETE22279.1 ETE48169.1 ETK29277.1 ETS33247.1 ETT01045.1 ETT07169.1 ETW14464.1 ETY41683.1 ETZ09941.1 EUB72243.1 EUB74618.1 EUB75427.1 EUB84551.1 EUB87030.1 EUB94968.1 EUB98403.1 EUC15772.1 EUC17426.1 EUC19927.1 EUC20682.1 EUD05937.1 EVU13232.1 EWG73750.1 EWH06794.1 EWS97919.1 EXB27436.1 EXB47610.1 EXL02912.1 EXL08805.1 EXU74154.1 EYD75827.1 EYD76005.1 EYD76216.1 EYD76391.1 EYD83437.1 EYR81340.1 EYT23778.1 EYU15951.1 EYV12183.1 EYV18352.1 EYZ99018.1 EZA32957.1 EZD33879.1 EZE09298.1 EZE49621.1 EZH78403.1 EZJ36630.1 EZJ49363.1 EZJ71201.1 EZJ83504.1 EZJ83557.1 EZK19944.1 EZP32763.1 EZP33753.1 EZP41224.1 EZP51786.1 EZP65628.1 EZQ15102.1 GAA61384.1 GAA61578.1 GAA64202.1 GAA65645.1 GAA67376.1 GAA68205.1 GAA78318.1 GAA80934.1 GAB51338.1 GAC32173.1 GAC65341.1 GAD00064.1 GAD00717.1 GAD03916.1 GAJ68144.1 GAK28093.1 GAK75263.1 GAK86396.1 GAK86397.1 GAK92924.1 GAK92925.1 GAK97920.1 GAK99145.1 GAL05071.1 GAL11041.1 GAL11042.1 GAL16782.1 GAL16859.1 GAL19427.1 GAL26771.1 GAL26853.1 GAL30714.1 GAL30715.1 GAL30716.1 GAL32582.1 GAL34679.1 GAL36803.1 GAL37656.1 GAL45646.1 GAL50932.1 GAL56692.1 GAL62430.1 GAL66823.1 GAL70387.1 GAL75242.1 GAL79182.1 GAL90464.1 GAL93895.1 GAL94496.1 GAM12739.1 GAM57916.1 GAM57917.1 GAM65556.1 GAM68524.1 GAM76289.1 GAP34694.1 GAP62607.1 GAP64452.1 GAP73496.1 GAR75760.1 KAJ04750.1 KAJ55629.1 KCV83816.1 KDA43421.1 KDA56888.1 KDA92361.1 KDB06864.1 KDB07503.1 KDC51678.1 KDF12959.1 KDF13306.1 KDG93655.1 KDM49647.1 KDM66049.1 KDN30188.1 KDO00731.1 KDO01789.1 KDR38345.1 KDR39580.1 KDR40471.1 KDR42489.1 KDR44448.1 KDR96261.1 KDU29241.1 KDV28115.1 KDV41545.1 KDV63795.1 KDW29938.1 KDX21120.1 KDX45706.1 KEA07283.1 KEA55087.1 KEA56995.1 KEA60549.1 KEF38453.1 KEI66155.1 KEI66563.1 KEI72808.1 KEJ44932.1 KEJ59125.1 KEJ73413.1 KEL65107.1 KEN53758.1 KEN65615.1 KEN98030.1 KEO08160.1 KEO20889.1 KEO30088.1 KEQ06864.1 KEQ11857.1 KEQ16616.1 KEQ56848.1 KEQ57225.1 KER03203.1 KER05877.1 KER71432.1 KER73555.1 KES24087.1 KEX93107.1 KEY59239.1 KEZ05720.1 KEZ05934.1 KFA97525.1 KFB10431.1 KFB86391.1 KFC05462.1 KFC26266.1 KFC50616.1 KFC63916.1 KFC75035.1 KFC77790.1 KFC78157.1 KFC79266.1 KFC88526.1 KFC95287.1 KFC98498.1 KFD07808.1 KFD17130.1 KFD75089.1 KFD81165.1 KFE26876.1 KFE29856.1 KFE36379.1 KFF88091.1 KFI27333.1 KFI27574.1 KFI32532.1 KFJ12154.1 KFK48033.1 KFK53897.1 KFK83392.1 KFL00125.1 KFL53690.1 KFM16262.1 KFM16471.1 KFM17679.1 KFM18828.1 KFM21122.1 KFN01206.1 KFX70429.1 KGA58376.1 KGB51681.1 KGB58219.1 KGB82923.1 KGB93469.1 KGB93751.1 KGC15448.1 KGD53502.1 KGD58420.1 KGD74931.1 KGD99322.1 KGE84568.1 KGF68819.1 KGF85749.1 KGF92571.1 KGF94969.1 KGF98296.1 KGG00684.1 KGG08593.1 KGG09329.1 KGG13720.1 KGG14534.1 KGG20576.1 KGG25389.1 KGJ87252.1 KGJ88564.1 KGJ88903.1 KGJ91830.1 KGJ98195.1 KGJ99182.1 KGJ99826.1 KGK11101.1 KGK24833.1 KGL02631.1 KGL61018.1 KGL63588.1 KGM06104.1 KGM27860.1 KGM47940.1 KGM62448.1 KGM71414.1 KGM83358.1 KGM85012.1 KGM87119.1 KGM89320.1 KGP46486.1 KGQ31158.1 KGQ42403.1 KGQ44024.1 KGQ45909.1 KGQ50254.1 KGQ57329.1 KGQ59396.1 KGQ63143.1 KGT92054.1 KGT93837.1 KGW03528.1 KGW13295.1 KGY09805.1 KGY14274.1 KHA72711.1 KHD09963.1 KHD12613.1 KHD26206.1 KHF30311.1 KHF30312.1 KHF32019.1 KHI37342.1 KHJ20007.1 KHJ52626.1 KHJ53009.1 KHJ67587.1 KHK58158.1 KHL14438.1 KHM50825.1 KHN63731.1 KHO62446.1 KHS44854.1 KHT65211.1 KIA76172.1 KIA79272.1 KIC08591.1 KIC11124.1 KIC12067.1 KIC20734.1 KIC21142.1 KIC38967.1 KIC39253.1 KIC42948.1 KIC44583.1 KIC48940.1 KIC81372.1 KID01688.1 KID07131.1 KID10239.1 KID53398.1 KIF44861.1 KIF47533.1 KIF60145.1 KIG04148.1 KIH04246.1 KII17028.1 KII76311.1 KIK88030.1 KIL14780.1 KIL44046.1 KIL49701.1 KIL52719.1 KIN13602.1 KIO35232.1 KIO64041.1 KIO64826.1 KIO64882.1 KIO74022.1 KIP13348.1 KIP19384.1 KIP21434.1 KIP28327.1 KIP77591.1 KIQ47214.1 KIQ67877.1 KIQ67879.1 KIQ93804.1 KIR21892.1 KIS42217.1 KIS44949.1 KIS45178.1 KIS78067.1 KIT15205.1 KIT26177.1 KIT34215.1 KIT53655.1 KIU06086.1 KIV63387.1 KIV67945.1 KIV69114.1 KIV76036.1 KIX18215.1 KIX35343.1 KIX40471.1 KIX50426.1 KIY38310.1 KJC02192.1 KJC05651.1 KJC11069.1 KJE27066.1 KJE29094.1 KJE37105.1 KJE41321.1 KJE56468.1 KJF68712.1 KJF74388.1 KJF82240.1 KJF95975.1 KJF96789.1 KJG26707.1 KJG38238.1 KJG58333.1 KJH08952.1 KIH75111.1 KJH76892.1 KJJ85191.1 KJJ97017.1 KJK05856.1 KJK14771.1 KJM40293.1 KJM86390.1 KJN20029.1 KJR24917.1 KJU79826.1 KIV49964.1 KJW32728.1 KJW52977.1 KJX12327.1 KJX88802.1 KJY81950.1 KJY91595.1 KJZ06665.1 KJZ10778.1 KJZ33490.1 KJZ43182.1 KJZ43642.1 KJZ49391.1 KJZ65470.1 KJZ83769.1 KJZ85311.1 KKA53929.1 KKB03409.1 KKC64603.1 KKC79077.1 KKD31623.1 KKD58710.1 KKD60086.1 KKF35468.1 KKI44370.1 KKJ02095.1 KKJ26483.1 KKJ76863.1 KKO14625.1 KKT03014.1 KKW50513.1 KKX34306.1 KKX57725.1 KKY43328.1 KKY65106.1 KKY79844.1 KKZ18900.1 KKZ94380.1 KLA23437.1 KLA28450.1 KLE26363.1 KLI68355.1 KLI96588.1 KLL00327.1 KLN47102.1 KLN59734.1 KLN96605.1 KLQ26950.1 KLS52970.1 KLT72171.1 KLU18616.1 KLU18617.1 KLU21135.1 KLU63532.1 KLV01110.1 KLV04731.1 KLV10916.1 KLV65168.1 KLW86529.1 KLX57832.1 KLX95653.1 KLY12051.1 KME68567.1 KMJ45199.1 KMJ52368.1 KMK12313.1 KMK65695.1 KMK67024.1 KML08951.1 KML19553.1 KML55768.1 KML63754.1 KMM44201.1 KMM80744.1 KMM88468.1 KMN35332.1 KMN52710.1 KMN54483.1 KMN64511.1 KMN82524.1 KMN90587.1 KMO70998.1 KMO75409.1 KMP15844.1 KMP32711.1 KMP76811.1 KMP97239.1 KMQ03530.1 KMQ27939.1 KMQ80607.1 KMT23186.1 KMV32028.1 KMV34546.1 KMV68971.1 KMV72039.1 KMW56860.1 KMW57564.1 KMW60148.1 KMW73818.1 KMY86054.1 KMZ11104.1 KNA43182.1 KNC12045.1 KNC94638.1 KND54403.1 KND57608.1 KND60713.1 KNF09788.1 KNF69260.1 KNF81881.1 KNH13933.1 KNH29699.1 KNH42940.1 KNN85891.1 KNW74428.1 KNX42579.1 KNX78696.1 KNY25361.1 KNY25362.1 KNY34664.1 KNY78419.1 KNZ84105.1 KNZ96650.1 KOA27319.1 KOA70223.1 KOC89788.1 KOC93579.1 KOE81497.1 KOE86385.1 KOF22188.1 KOO07592.1 KOO13953.1 KOP04210.1 KOP34818.1 KOR21593.1 KOY02635.1 KOY33005.1 KOY45864.1 KOY61141.1 KPA10469.1 KPA16733.1 KPA20218.1 KPA53392.1 KPB01772.1 KPC99823.1 KPD03212.1 KPD11463.1 KPD14945.1 KPD18730.1 KPF43120.1 KPF56119.1 KPF72724.1 KPG94733.1 KPG95797.1 KPH01583.1 KPH10681.1 KPH60166.1 KPH81257.1 KPL51015.1 KPL87226.1 KPL88374.1 KPL99047.1 KPM59181.1 KPM65351.1 KPM84873.1 KPM96585.1 KPN62270.1 KPN70840.1 KPN74193.1 KPN90785.1 KPO18578.1 KPO36864.1 KPO46574.1 KPP84622.1 KPP85678.1 KPP85884.1 KPP89409.1 KPQ06101.1 KPQ08097.1 KPQ13684.1 KPQ14340.1 KPQ14479.1 KPQ21467.1 KPQ22810.1 KPQ29983.1 KPQ32046.1 KPQ36131.1 KPQ37310.1 KPR57622.1 KPU50749.1 KPU53876.1 KPU54584.1 KPU54773.1 KPU84621.1 KPW02372.1 KPW04291.1 KPZ52050.1 KPZ54771.1 KPZ63440.1 KPZ65777.1 KPZ67737.1 KPZ69053.1 KPZ72596.1 KQA23172.1 KQA98185.1 KQB15598.1 KQB16357.1 KQB91620.1 KQB98549.1 KQJ13932.1 KQJ46046.1 KST27455.1 KSX90871.1 KTH73166.1 KTM92472.1 KTO38350.1 KTO86996.1 KTP62451.1 KUH44100.1 KUI50798.1 KUQ52563.1 KUU48154.1 KWV87278.1 KWZ91247.1 KXG92414.1 KXH00366.1 KXH98341.1 KXI61250.1 KXJ38653.1 KXL66969.1 KXQ42781.1 KXX90622.1 KXY08066.1 KXY28981.1 KXY53137.1 KXY72091.1 KYR44967.1 KYS97777.1 KYV67952.1 KZD58224.1 KZD81457.1 KZD82131.1 KZE06157.1 KZJ59530.1 OAC43113.1 OAE40342.1 OAE92625.1 OAH32122.1 OAJ87923.1 OAO68288.1 OAO72922.1 OBX00501.1 OCS74956.1 OCS95951.1 OCV53559.1 ODH24471.1 OEG92891.1 OEH04368.1 OEH12481.1 OEH14141.1 OEH95893.1 OEI65538.1 OEN36597.1 OIN26435.1 OIR51681.1 OIX27476.1 SAD71408.1 SAE32773.1 SAI34905.1 SAY76569.1 SAZ57795.1 SBX90640.1 SBZ90882.1 SCM53106.1

Representative examples of ornithine decarboxylase (EC 4.1.1.17) are given below in Table 9 and identified by their EMBL/GENBANK/DDBJ ID numbers. Any of the bacteria given in Table 10 can be engineered with any version of the ornithine decarboxylase (EC 4.1.1.17) set forth in Table 3 and 9. For instance, the bacteria can be engineered with a version of the ornithine decarboxylase enzyme that has at least 50% nucleotide similarity with any of the versions of ornithine decarboxylase given in Table 9 (e.g., at least nucleotide 60% similarity, at least 70% nucleotide similarity, at least 80% nucleotide similarity, at least 90% nucleotide similarity, at least 91% nucleotide similarity, at least 92% nucleotide similarity, at least 93% nucleotide similarity, at least 94% nucleotide similarity, at least 95% nucleotide similarity, at least 96% nucleotide similarity, at least 97% nucleotide similarity, at least 98% nucleotide similarity, at least 99% nucleotide similarity, at least 99.5% nucleotide similarity, at least 99.9% nucleotide similarity, or 100% nucleotide similarity).

TABLE 9 Representative Examples of Ornithine Decarboxylase by EMBL/GENBANK/DDBJ ID Number AAA62785.1 AAN66489.2 ABB12186.1 ABE38094.1 AAA66174.1 AAN79250.1 ABB40870.1 ABE44334.1 AAA69133.1 AAN82001.1 ABB75259.1 ABE49183.1 AAC22248.1 AAO90264.2 ABC22493.1 ABE49327.1 AAC73787.1 AAS63636.1 ABC92384.1 ABE56353.1 AAC76002.2 AAV42846.1 ABD09230.1 ABE64149.1 AAK65018.1 AAW60223.1 ABD53718.1 ABE73821.1 AAK65019.2 AAY39277.1 ABD69850.1 ABF62084.1 AAL19645.1 AAY96264.1 ABD82224.1 ABF76724.1 AAL21989.1 AAZ17903.1 ABD90359.1 ABF79243.1 AAL54375.1 AAZ21026.1 ABD98955.1 ABG12272.1 AAL94697.1 AAZ45335.1 ABE05711.1 ABG19485.1 AAM32881.1 AAZ60071.1 ABE06188.1 ABG64092.1 AAM86897.1 AAZ71105.1 ABE08804.1 ABI25841.1 AAN53399.1 ABA04186.1 ABE29508.1 ABI41283.1 AAN57109.1 ABA78141.1 ABE36633.1 ABI41448.1 ABI59635.1 ABQ46942.1 ACF00856.1 ADG60285.1 ABI61420.1 ABQ77056.1 ACF62498.1 ADI02315.1 ABI64670.1 ABQ77881.1 ACF64187.1 ADM40347.1 ABI73241.1 ABQ94106.1 ACG58193.1 ADM42835.1 ABI88035.1 ABR63972.1 ACH49712.1 ADM42836.1 ABJ07102.1 ABR71097.1 ACH50260.1 ADM97227.1 ABJ08721.1 ABS65893.1 ACH63785.1 ADO10738.1 ABJ70427.1 ABS77454.2 ACI11630.1 ADO47055.1 ABK39746.1 ABV20152.1 ACI98761.1 ADO49370.1 ABK49901.1 ABV20217.1 ACI99115.1 ADO84265.1 ABK50089.1 ABV32717.1 ACJ00377.1 ADP99549.1 ABL98620.1 ABV39617.1 ACK48448.1 ADU45025.1 ABM01537.1 ABV43142.1 ACK49205.1 ADU70535.1 ABM03233.1 ABV93117.1 ACK81873.1 ADU91399.1 ABM17184.1 ABX51330.1 ACK83165.1 ADV11066.1 ABM33819.1 ABY29398.1 ACL55330.1 ADV56349.1 ABM37329.1 ABY96818.1 ACL93832.1 ADW75162.1 ABM42903.1 ACA15010.1 ACN14131.1 ADY12020.1 ABM94883.1 ACA32083.1 ACP07980.1 ADZ25852.1 ABN63325.1 ACA67112.1 ACP26670.1 ADZ25990.1 ABN63550.1 ACA74794.1 ACQ92481.1 AEA25536.1 ABO25258.1 ACA92668.1 ACR70548.1 AEA80789.1 ABO55514.1 ACB16558.1 ACR80274.1 AEB13218.1 ABP59886.1 ACB17513.1 ACS38696.1 AEE17405.1 ABP62042.1 ACB26370.1 ACS39829.1 AEF20700.1 ABP74273.1 ACB26621.1 ACS86807.1 AEF54819.1 ABP77387.1 ACB79112.1 ACT08032.1 AEG05601.1 ABP83569.1 ACB94577.1 ACT11922.1 AEG07021.1 ABQ13490.1 ACC75475.1 ACX89156.1 AEG09620.1 ABQ18377.1 ACD09708.1 ACY53777.1 AEG09845.1 ABQ31378.1 ACE89117.1 ACZ75768.1 AEG48476.1 ABQ33584.1 ACE92836.1 ADA66726.1 AEH50365.1 ABQ35247.1 ACE99495.1 ADE84258.1 AEH86445.1 AEI07722.1 AIJ07696.1 AKB72738.1 BAQ17945.1 AEJ18813.1 AIJ08459.1 AKB75272.1 BAU72598.1 AEK61463.1 AIQ92829.1 AKB78060.1 CAD78655.1 AEM41039.1 AIQ93098.1 AKB81641.1 CAD84820.1 AEP37160.1 AIR09930.1 AKB84150.1 CAG69512.1 AEV60919.1 AIT00368.1 AKF49823.1 CAG73878.1 AFJ59017.1 AIZ81713.1 AKH27073.1 CAH22470.1 AFL53867.1 AIZ84023.1 AKH69183.1 CAI97377.1 AFY17936.1 AJE57512.1 AKH99554.1 CAI98549.1 AFY20265.1 AJF55421.1 AKO77226.1 CAJ12264.1 AGA64911.1 AJF57769.1 AKO97889.1 CAK02040.1 AGG15787.1 AJG20615.1 ALD27842.1 CAK13937.1 AGG70048.1 AJI87080.1 ALV76207.1 CAL10580.1 AGG70049.1 AJK49051.1 ALY14469.1 CAL13549.1 AGH98733.1 AJQ96966.1 ALZ68204.1 CAL19626.1 AGL50812.1 AKA84438.1 ALZ69985.1 CAL78631.1 AGO56945.1 AKB12437.1 ANK35386.1 CAL79901.1 AGT07607.1 AKB14359.1 ANM83745.1 CAM00591.1 AHA66979.1 AKB18263.1 ANM85435.1 CAM03603.1 AHD10069.1 AKB21587.1 ANP16911.1 CAO97896.1 AHD10849.1 AKB25327.1 AOM43847.1 CAQ81820.1 AHE50504.1 AKB28151.1 AOT33749.1 CAQ89917.1 AHE58679.1 AKB32085.1 APF08471.1 CAQ90401.1 AHF70264.1 AKB37309.1 APF13004.1 CAR02067.1 AHF74955.1 AKB40448.1 BAA35349.1 CAR04482.1 AHH20127.1 AKB43558.1 BAE77028.1 CAR06878.1 AHJ62296.1 AKB47010.1 BAI71258.1 CAR09582.2 AHK70374.1 AKB51817.1 BAI72082.1 CAR14483.1 AHM04085.1 AKB55259.1 BAI76414.1 CAR16788.1 AHM04146.1 AKB56666.1 BAI96560.1 CAR19506.1 AHM77647.1 AKB61403.1 BAJ81775.1 CAR36594.1 AHM83238.1 AKB64701.1 BAL83346.1 CAR40820.1 AHY72323.1 AKB68292.1 BAN98715.1 CAR54968.1 CAU96547.1 CCD85313.1 CC007100.1 CDL50778.1 CAU99265.1 CCD87735.1 CCQ09200.1 CDL50819.1 CAX18544.1 CCD96638.1 CCQ74399.1 CDL86182.1 CAX22758.1 CCE00128.1 CCT59416.1 CDL90667.1 CAX24467.1 CCE04953.1 CCU62281.1 CDM25489.1 CAX61217.1 CCE05308.1 CCU62303.1 CDM39302.1 CAX67648.1 CCE97429.1 CCV05533.1 CDM59281.1 CAX67666.1 CCE98566.1 CCV16052.1 CDM60694.1 CAY75622.1 CCF20520.1 CCW14223.1 CDN08374.1 CBA19528.1 CCG07833.1 CCW18613.1 CDO59353.1 CBA28212.1 CCG39584.1 CDF57711.1 CDP53980.1 CBA29223.1 CCG86023.1 CDF82218.1 CDQ16217.1 CBA33757.1 CCG93567.1 CDF92784.1 CDR81373.1 CBG87473.1 CCI82390.1 CDF95827.1 CDR83974.1 CBG91695.1 CCJ43149.1 CDG34413.1 CDR89923.1 CBI76815.1 CCJ73160.1 CDG41242.1 CDS49197.1 CBI78256.1 CCJ73613.1 CDI09982.1 CDU34381.1 CBI78275.1 CCJ79388.1 CDK34386.1 CDU39548.1 CBL06633.1 CCJ82552.1 CDK72259.1 CDU41134.1 CBS85874.1 CCJ86161.1 CDK72653.1 CDX11380.1 CBS86483.1 CCJ87942.1 CDK75666.1 CDX28277.1 CBS89897.1 CCJ89861.1 CDK97758.1 CDX31971.1 CBW16782.1 CCJ91600.1 CDK98655.1 CDX32761.1 CBW19188.1 CCJ97363.1 CDL07277.1 CDX44074.1 CBY25820.1 CCJ99535.1 CDL10022.1 CDX54921.1 CBY25832.1 CCK01641.1 CDL20226.1 CDX58455.1 CBY28841.1 CCK03853.1 CDL23839.1 CDY74095.1 CCA93756.1 CCK06057.1 CDL25819.1 CEF30930.1 CCC57896.1 CCK08478.1 CDL25820.1 CEG53321.1 CCC96226.1 CCK22783.1 CDL27267.1 CEI15979.1 CCC98554.1 CCK45849.1 CDL27268.1 CEJ65390.1 CCD02602.1 CCK48255.1 CDL27269.1 CEK26252.1 CCD40282.1 CCM77346.1 CDL39170.1 CEK27948.1 CEL27520.1 CSC55030.1 CTS78438.1 EDQ31943.2 CEL88226.1 CSC90483.1 CTT62185.1 EDQ34501.1 CEP77894.1 CSC91956.1 CTT62210.1 EDR33413.1 CFQ53013.1 CSI90225.1 CTT77363.1 EDS92093.1 CFQ53087.1 CSI94697.1 CTT83136.1 EDU62245.1 CFQ53093.1 CSK70247.1 CTT84900.1 EDU64911.1 CFQ63135.1 CSL03024.1 CTT94762.1 EDU91579.1 CNJ42662.1 CSL07641.1 CTU09480.1 EDU92556.1 CNK09967.1 CSM63721.1 CTU43474.1 EDX33853.1 CPR14076.1 CSM98897.1 CTU46798.1 EDX36097.1 CPR26377.1 CSN54919.1 CTU67775.1 EDX47281.1 CPR26378.1 CSP82502.1 CTV17999.1 EDX48079.1 CQH28513.1 CSP97222.1 CTV22603.1 EDY22541.1 CQH50344.1 CSR81748.1 CTV49713.1 EDY26086.1 CRG52628.1 CSS46262.1 CTV56172.1 EDZ45245.1 CRH30711.1 CSS69716.1 CTV59366.1 EDZ48441.1 CRH35440.1 CST05596.1 CTV99708.1 EDZ60503.1 CRH39733.1 CTQ00658.1 CTW90830.1 EEB70922.1 CRL10245.1 CTQ07290.1 CTX56302.1 EEB72505.1 CRL11665.1 CTQ10899.1 CTZ36862.1 EEH90224.1 CRL87218.1 CTQ21239.1 CTZ54946.1 EEI47014.1 CRO16551.1 CTQ33367.1 CTZ68478.1 EEI67673.1 CRP80377.1 CTQ42919.1 CTZ90267.1 EEJ60488.1 CRY55295.1 CTQ43401.1 CUH38863.1 EEJ72107.1 CRY56151.1 CTQ48990.1 CUH97680.1 EEJ73250.1 CRY73398.1 CTQ51582.1 CUI46350.1 EEN80026.1 CRZ77491.1 CTQ64509.1 CUI65295.1 EE001571.1 CSA30444.1 CTQ70679.1 CUJ95194.1 EEO17726.1 CSB23271.1 CTQ77678.1 CUK08178.1 EEQ24327.1 CSB44423.1 CTR81841.1 EAA24580.1 EEV22915.1 CSB97832.1 CTR87483.1 EDL69175.1 EEW41165.1 CSC29054.1 CTS06036.1 EDM60163.1 EEX49266.1 CSC32042.1 CTS29676.1 EDN58782.1 EEY45602.1 EEY99726.1 EGK26884.1 E1Q71312.1 ENA38238.1 EFC91687.1 EGK34653.1 EIQ76994.1 ENA43866.1 EFE96168.1 EGK34656.1 EIQ78394.1 ENC90052.1 EFE96169.1 EGK40304.1 EIZ02840.1 END51232.1 EFE97489.1 EGK58241.1 EJI92011.1 END90160.1 EFG55431.1 EGK62838.1 EJL03608.1 ENG95671.1 EFM19932.1 EGL98455.1 EJL08507.1 ENH01203.1 EFM60159.1 EGL98460.1 EJO49529.1 ENH07634.1 EFP71802.1 EGM68475.1 EK150690.1 EOD01056.1 EFQ23396.1 EGM68534.1 EKP99013.1 EPA96228.1 EFQ65259.1 EGO94943.1 EKP99014.1 EPC15663.1 EFR18105.1 EGP08625.1 EKQ02803.1 EPC38567.1 EFR18206.1 EGP13188.1 EKQ02804.1 EPF66737.1 EFW49207.1 EHC87901.1 EKQ09991.1 EPX75972.1 EFW49866.1 EHC94859.1 EKQ09992.1 EPX79893.1 EFW55944.1 EHC94874.1 EKQ11508.1 EPX85529.1 EFW57461.1 EHD22909.1 EKQ11509.1 EPX86372.1 EFW59125.1 EHE87725.1 EKQ18817.1 EQC66601.1 EFY04546.1 EHE90319.1 EKQ21433.1 EQC67119.1 EFZ35827.1 EHP88849.1 EKS52809.1 ERJ07090.1 EGC73182.1 EHP90237.1 ELS26426.1 ERJ12441.1 EGD26721.1 EHU02113.1 ELW31551.1 ERL16034.1 EGF12882.1 EHU20119.1 EMS72676.1 ERL56578.1 EGF12883.1 EHU26736.1 EMU59716.1 ESN64144.1 EGF13575.1 EHV55210.1 EMU68355.1 ESN64681.1 EGF13579.1 E1C02033.1 EMV17894.1 ESR23196.1 EGI92040.1 EIJ31771.1 EMW96757.1 ESR27061.1 EGI93253.1 EIK63890.1 EMX18650.1 ESS57441.1 EGI99407.1 EIK67948.1 EMX29506.1 ESU78166.1 EGJ01620.1 EIK70882.1 EMX36739.1 ETA69456.1 EGK15386.1 EIQ05587.1 EMX46897.1 ETS92400.1 EGK19303.1 EIQ18576.1 EMX83235.1 EUB20316.1 EGK26882.1 EIQ26095.1 ENA04683.1 EUB71374.1 EUB75197.1 KEJ45027.1 KGM62416.1 KMO67617.1 EUB84084.1 KEJ59156.1 KGM68326.1 KMO73993.1 EUB97023.1 KEJ73445.1 KGM71386.1 KMO74679.1 EUC12442.1 KEK27105.1 KGM77872.1 KMQ72910.1 EWC58917.1 KEK29881.1 KGM80580.1 KMY85028.1 EWC60810.1 KEL65139.1 KGM83330.1 KMZ12404.1 EWG73717.1 KEN53788.1 KGM84983.1 KND54388.1 EWG77348.1 KEN65519.1 KGM87536.1 KND59806.1 EYD71048.1 KEN98059.1 KGM88313.1 KNE76189.1 EYD71269.1 KEO08191.1 KHJ19976.1 KNF62494.1 EYD77132.1 KEO30074.1 KHN90703.1 KNF81913.1 EYD83397.1 KEQ53465.1 KHQ55244.1 KNF82765.1 EZJ36659.1 KER02947.1 KID27997.1 KNH02424.1 EZJ49393.1 KEY57491.1 KIH04277.1 KNH10085.1 EZJ71231.1 KEZ18534.1 KIQ45687.1 KNX39995.1 EZJ83500.1 KFC03280.1 KIQ47241.1 KNX42257.1 EZK19977.1 KFC05486.1 KIQ68453.1 KOA19269.1 EZP30980.1 KFC63691.1 KIQ68551.1 KON65543.1 EZP72267.1 KFC69417.1 KIR02360.1 KPA20904.1 GAO78552.1 KFC77644.1 KIR22223.1 KPA88263.1 GAP76203.1 KFC79295.1 KIS02883.1 KPO11674.1 KDA56789.1 KFC83942.1 KIT17643.1 KPO18606.1 KDE39162.1 KFC88765.1 KIV66814.1 KPO45157.1 KDM66230.1 KFC94984.1 KIV70876.1 KPO46605.1 KDM67094.1 KFD06768.1 KJL37417.1 KPP86129.1 KDM68717.1 KFD07842.1 KJL45196.1 KPQ30708.1 KDR44432.1 KFD17151.1 KJW30930.1 KPW02487.1 KDU29207.1 KFE39747.1 KJX87011.1 KPZ58476.1 KDW29935.1 KFE40588.1 KLU03251.1 KPZ73698.1 KDX21151.1 KFL92212.1 KLY03824.1 KQJ13961.1 KDX45737.1 KGA92942.1 KMK68540.1 KQJ37165.1 KEA62619.1 KGB23003.1 KMM41085.1 KRK54316.1 KEC54001.1 KGM59804.1 KMM41943.1 KRK64371.1 KSH09715.1 KYV67923.1 OCV53530.1 OJF06953.1 KST27486.1 KYV72148.1 ODH24445.1 SAY77725.1 KTZ13476.1 OAC43139.1 OEI63490.1 SEF59356.1 KXL65724.1 OAH24264.1 OEI65510.1 KXQ42753.1 OAJ89982.1 OFJ34340.1 KYR53760.1 OCS73051.1 OIR53362.1

A variety of microbes (e.g., bacteria) can be engineered to produce GABA (e.g., by engineering one or more of the enzymes set forth in Table 2). For instance, any of the bacteria set forth in Table 10 can be engineered to produce GABA. In other words, a bacteria having a 16S rDNA nucleotide sequence that is at least 50% similar to that set forth in Table 10 below can be engineered (e.g., with one of the enzymes in Tables 3-9) to produce GABA. The bacteria may have a 16S rDNA sequence that is at least 60% similar, at least 70% similar, at least 80% similar, at least 90% similar, at least 91% similar, at least 92% similar, at least 93% similar, at least 94% similar, at least 95% similar, at least 96% similar, at least 97% similar, at least 98% similar, at least 99% similar, at least 99.5% similar, or 100% similar to the 16S rDNA nucleotide sequence given in Table 10.

As set forth in Example 8, E. coli was engineered to overexpress glutamate decarboxylase, which without wishing to be bound by theory, led to the expression of GABA by the engineered E. coli. As shown in FIGS. 6A-E, the engineered E. coli was able to induce the growth of E. gabavorous KLE1738. GABA can be produced by intestinal epithelial cells and by some bacteria, such as Escherichia coli and Listeria monocytogenes, by decarboxylation of glutamate. In E. coli, the decarboxylation of glutamate can serve as a mechanism to decrease intracellular pH, and therefore in some embodiments GABA production generally occurs at a low pH.

As set forth in Example 8, Expression, e.g., overexpression of glutamate decarboxylase in E. coli (e.g., gadA or gadB), resulted in induction of E. gabavorous KLE1738 growth to levels seen with B. fragilis KLE 1758. For instance, FIG. 6A shows induction of E. gabavorous KLE1738 in the presence of E. coli engineered to express glutamate decarboxylase gadA. Similarly, FIG. 6B shows induction of E. gabavorous KLE1738 in the presence of E. coli engineered to express glutamate decarboxylase gadB. As shown in FIG. 6C, the growth of E. gabavorous KLE1738 was qualitatively similar to that seen in the presence of B. fragilis KLE 1758. In contrast, as shown in FIG. 6D, when E. coli was engineered to express gadC, a GABA antiporter, no growth of E. gabavorous KLE1738 was observed. Similarly, no growth of E. gabavorous KLE1738 was observed in the presence of empty vehicle (FIG. 6E). Without wishing to be bound by theory the results of Example 8 demonstrate that bacteria can be engineered to produce GABA (e.g., via the expression or overexpression of glutamate decarboxylase). In some embodiments, the bacteria (e.g., E. coli) can be engineered to produce GABA inside the human gut.

In some embodiments, the present disclosure also provides compromising one or more repressors of GABA production, (e.g., gadX or gadW). In some embodiments, these repressors can regulate the pH restrictions of GABA production in E. coli, is a way to increase native GABA production. This can be achieved, for instance, via gene deletions, insertions, or substitutions, as known by those skilled in the art of molecular biology.

Altering the pH of growth media for KLE1738 did not change the GABA-dependency phenotype. Without wishing to be bound by theory, this suggests that engineering bacteria to overexpress glutamate decarboxylase is an effective way to produce GABA, as well as induce the growth of E. gabavorous.

In addition to E. coli, other bacteria can be engineered to produce GABA (e.g., at a physiologically relevant pH, such as between 4.5 and 7.5). For instance, any of the bacteria set forth in Table 10 can be engineered to produce GABA (e.g., at a physiologically relevant pH, such as between 4.5 and 7.5). For example, the bacteria can be engineered to contain DNA that codes for one or more enzymes set forth in Table 3-9. Set forth in Table 10 is also a sequence ID number for the 16S nucleotide sequence of the listed bacteria. In some embodiments, the bacteria that are engineered to produce GABA can have at least 90% 16S sequence similarity to the 16S sequences given in Table 10 (e.g., at least 91% similarity, at least 92% similarity, at least 93% similarity, at least 94% similarity, at least 95% similarity, at least 96% similarity, at least 97% similarity, at least 98% similarity, at least 99% similarity, at least 99.5% similarity, at least 99.9% similarity, or 100% similarity).

TABLE 10 Bacteria Capable of Being Engineered to Produce GABA Species Seq. ID No. Abiotrophia defectiva 305 Abiotrophia para-adiacens 306 Abiotrophia sp. 307 Acetanaerobacterium elongatum 308 Acetivibrio cellulolyticus 309 Acetivibrio ethanolgignens 310 Acetobacter aceti 311 Acetobacter fabarum 312 Acetobacter lovaniensis 313 Acetobacter malorum 314 Acetobacter orientalis 315 Acetobacter pasteurianus 316 Acetobacter pomorum 317 Acetobacter syzygii 318 Acetobacter tropicalis 319 Acetobacteraceae bacterium 320 Acholeplasma laidlawii 321 Achromobacter denitrificans 322 Achromobacter piechaudii 323 Achromobacter xylosoxidans 324 Acidaminococcus fermentans 325 Acidaminococcus intestini 326 Acidaminococcus sp. 327 Acidilobus saccharovorans 328 Acidithiobacillus ferrivorans 329 Acidovorax sp. 330 Acidovorax sp. 331 Acinetobacter baumannii 332 Acinetobacter calcoaceticus 333 Acinetobacter genomo sp. 334 Acinetobacter haemolyticus 335 Acinetobacter johnsonii 336 Acinetobacter junii 337 Acinetobacter lwoffii 338 Acinetobacter parvus 339 Acinetobacter radioresistens 340 Acinetobacter schindleri 341 Acinetobacter sp. 342 Acinetobacter sp. 343 Acinetobacter sp. 344 Acinetobacter sp. 345 Acinetobacter sp. 346 Acinetobacter sp. 347 Acinetobacter sp. 348 Actinobacillus minor 349 Actinobacillus pleuropneumoniae 350 Actinobacillus succinogenes 351 Actinobacillus succinogenes 352 Actinobacillus ureae 353 Actinobaculum massiliae 354 Actinobaculum schaalii 355 Actinobaculum sp. 356 Actinobaculum sp. 357 Actinomyces cardiffensis 358 Actinomyces europaeus 359 Actinomyces funkei 360 Actinomyces genomo sp. 361 Actinomyces genomo sp. 362 Actinomyces genomo sp. 363 Actinomyces georgiae 364 Actinomyces israelii 365 Actinomyces massiliensis 366 Actinomyces meyeri 367 Actinomyces naeslundii 368 Actinomyces nasicola 369 Actinomyces neuii 370 Actinomyces odontolyticus 371 Actinomyces oricola 372 Actinomyces orihominis 373 Actinomyces oris 374 Actinomyces sp. 375 Actinomyces sp. 376 Actinomyces sp. 377 Actinomyces sp. 378 Actinomyces sp. 379 Actinomyces sp. 380 Actinomyces sp. 381 Actinomyces sp. 382 Actinomyces sp. 383 Actinomyces sp. 384 Actinomyces sp. 385 Actinomyces sp. 386 Actinomyces sp. 387 Actinomyces sp. 388 Actinomyces sp. 389 Actinomyces sp. 390 Actinomyces sp. 391 Actinomyces sp. 392 Actinomyces sp. 393 Actinomyces sp. 394 Actinomyces sp. 395 Actinomyces sp. 396 Actinomyces sp. 397 Actinomyces sp. 398 Actinomyces sp. 399 Actinomyces urogenitalis 400 Actinomyces viscosus 401 Adlercreutzia equolifaciens 402 Aerococcus sanguinicola 403 Aerococcus urinae 404 Aerococcus urinaeequi 405 Aerococcus viridans 406 Aeromicrobium marinum 407 Aeromicrobium sp. 408 Aeromonas allosaccharophila 409 Aeromonas enteropelogenes 410 Aeromonas hydrophila 411 Aeromonas jandaei 412 Aeromonas salmonicida 413 Aeromonas trota 414 Aeromonas veronii 415 Afipia genomo sp. 416 Aggregatibacter actinomycetemcomitans 417 Aggregatibacter aphrophilus 418 Aggregatibacter segnis 419 Agrobacterium radiobacter 420 Agrobacterium tumefaciens 421 Agrococcus jenensis 422 Akkermansia mucimphila 423 Alcaligenes faecalis 424 Alcaligenes sp. 425 Alcaligenes sp. 426 Alicyclobacillus acidocaldarius 427 Alicyclobacillus acidoterrestris 428 Alicyclobacillus contaminans 429 Alicyclobacillus cycloheptanicus 430 Alicyclobacillus herbarius 431 Alicyclobacillus pomorum 432 Alicyclobacillus sp. 433 Alistipes finegoldii 434 Alistipes indistinctus 435 Alistipes onderdonkii 436 Alistipes putredinis 437 Alistipes shahii 438 Alistipes sp. 439 Alistipes sp. 440 Alistipes sp. 441 Alkahphilus metalliredigenes 442 Alkahphilus oremlandii 443 Alloscardovia omnicolens 444 Alloscardovia sp. 445 Anaerobaculum hydrogenfformans 446 Anaerobiospirillum succiniciproducens 447 Anaerobiospirillum thomasii 448 Anaerococcus hydrogenalis 449 Anaerococcus lactolyticus 450 Anaerococcus octavius 451 Anaerococcus prevotii 452 Anaerococcus sp. 453 Anaerococcus sp. 454 Anaerococcus sp. 455 Anaerococcus sp. 456 Anaerococcus sp. 457 Anaerococcus sp. 458 Anaerococcus sp. 459 Anaerococcus sp. 460 Anaerococcus sp. 461 Anaerococcus tetradius 462 Anaerococcus vaginalis 463 Anaerofustis stercorihominis 464 Anaeroglobus geminatus 465 Anaerosporobacter mobilis 466 Anaerostipes caccae 467 Anaerostipes sp. 468 Anaerotruncus colihominis 469 Anaplasma marginate 470 Anaplasma phagocytophilum 471 Aneurinibacillus aneurinilyticus 472 Aneurinibacillus danicus 473 Aneurinibacillus migulanus 474 Aneurinibacillus terranovensis 475 Aneurinibacillus thermoaerophilus 476 Anoxybacillus contaminans 477 Anoxybacillus flavithermus 478 Arcanobacterium haemolyticum 479 Arcanobacterium pyogenes 480 Arcobacter butzleri 481 Arcobacter cryaerophilus 482 Arthrobacter agilis 483 Arthrobacter arilaitensis 484 Arthrobacter bergerei 485 Arthrobacter globiformis 486 Arthrobacter nicotianae 487 Atopobium minutum 488 Atopobium parvulum 489 Atopobium rimae 490 Atopobium sp. 491 Atopobium sp. 492 Atopobium sp. 493 Atopobium sp. 494 Atopobium vaginae 495 Aurantimonas coralicida 496 Aureimonas altamirensis 497 Auritibacter ignavus 498 Averyella dalhousiensis 499 Bacillus aeolius 500 Bacillus aerophilus 501 Bacillus aestuarii 502 Bacillus alcalophilus 503 Bacillus amyloliquefaciens 504 Bacillus atrophaeus 505 Bacillus badius 506 Bacillus cereus 507 Bacillus circulans 508 Bacillus clausii 509 Bacillus coagulans 510 Bacillus firmus 511 Bacillus flexus 512 Bacillus fordii 513 Bacillus gelatini 514 Bacillus halmapalus 515 Bacillus halodurans 516 Bacillus herbersteinensis 517 Bacillus horti 518 Bacillus idriensis 519 Bacillus lentus 520 Bacillus licheniformis 521 Bacillus megaterium 522 Bacillus nealsonii 523 Bacillus niabensis 524 Bacillus niacini 525 Bacillus pocheonensis 526 Bacillus pumilus 527 Bacillus safensis 528 Bacillus simple 529 Bacillus sonorensis 530 Bacillus sp. 531 Bacillus sp. 532 Bacillus sp. 533 Bacillus sp. 534 Bacillus sp. 535 Bacillus sp. 536 Bacillus sp. 537 Bacillus sp. 538 Bacillus sp. 539 Bacillus sp. 540 Bacillus sp. 541 Bacillus sp. 542 Bacillus sp. 543 Bacillus sp. 544 Bacillus sp. 545 Bacillus sp. 546 Bacillus sp. 547 Bacillus sp. 548 Bacillus sp. 549 Bacillus sp. 550 Bacillus sp. 551 Bacillus sp. 552 Bacillus sp. 553 Bacillus sp. 554 Bacillus sphaericus 555 Bacillus sporothermodurans 556 Bacillus subtilis 557 Bacillus thermoamylovorans 558 Bacillus thuringiensis 559 Bacillus weihenstephanensis 560 Bacteroidales bacterium 561 Bacteroidales genomo sp. 562 Bacteroidales genomo sp. 563 Bacteroidales genomo sp. 564 Bacteroidales genomo sp. 565 Bacteroidales genomo sp. 566 Bacteroidales genomo sp. 567 Bacteroidales genomo sp. 568 Bacteroidales genomo sp. 569 Bacteroides acidifaciens 570 Bacteroides barnesiae 571 Bacteroides caccae 572 Bacteroides cellulosilyticus 573 Bacteroides clarus 574 Bacteroides coagulans 575 Bacteroides coprocola 576 Bacteroides coprophilus 577 Bacteroides dorei 578 Bacteroides eggerthii 579 Bacteroides faecis 580 Bacteroides finegoldii 581 Bacteroides fluxus 582 Bacteroides fragilis 583 Bacteroides galacturonicus 584 Bacteroides hekogenes 585 Bacteroides heparinolyticus 586 Bacteroides intestinalis 587 Bacteroides massiliensis 588 Bacteroides nordii 589 Bacteroides oleiciplenus 590 Bacteroides ovatus 591 Bacteroides pectinophilus 592 Bacteroides plebeius 593 Bacteroides pyogenes 594 Bacteroides salanitronis 595 Bacteroides salyersiae 596 Bacteroides sp. 597 Bacteroides sp. 598 Bacteroides sp. 599 Bacteroides sp. 600 Bacteroides sp. 601 Bacteroides sp. 602 Bacteroides sp. 603 Bacteroides sp. 604 Bacteroides sp. 605 Bacteroides sp. 606 Bacteroides sp. 607 Bacteroides sp. 608 Bacteroides sp. 609 Bacteroides sp. 610 Bacteroides sp. 611 Bacteroides sp. 612 Bacteroides sp. 613 Bacteroides sp. 614 Bacteroides sp. 615 Bacteroides sp. 616 Bacteroides sp. 617 Bacteroides sp. 618 Bacteroides sp. 619 Bacteroides sp. 620 Bacteroides sp. 621 Bacteroides sp. 622 Bacteroides sp. 623 Bacteroides sp. 624 Bacteroides sp. 625 Bacteroides sp. 626 Bacteroides sp. 627 Bacteroides sp. 628 Bacteroides sp. 629 Bacteroides sp. 630 Bacteroides sp. 631 Bacteroides stercoris 632 Bacteroides thetaiotaomicron 633 Bacteroides uniformis 634 Bacteroides ureolyticus 635 Bacteroides vulgatus 636 Bacteroides xylanisolvens 637 Bacteroidetes bacterium 638 Bacteroidetes bacterium 639 Bacteroidetes bacterium 640 Barnesiella intestinihominis 641 Barnesiella viscericola 642 Bartonella bacilliformis 643 Bartonella grahamii 644 Bartonella henselae 645 Bartonella quintana 646 Bartonella tamiae 647 Bartonella washoensis 648 Bdellovibrio sp. 649 Bifidobacteriaceae genomo sp. 650 Bifidobacterium adolescentis 651 Bifidobacterium angulatum 652 Bifidobacterium animalis 653 Bifidobacterium bifidum 654 Bifidobacterium breve 655 Bifidobacterium catenulatum 656 Bifidobacterium gallicum 657 Bifidobacterium infantis 658 Bifidobacterium kashiwanohense 659 Bifidobacterium longum 660 Bifidobacterium pseudocatenulatum 661 Bifidobacterium pseudolongum 662 Bifidobacterium scardovii 663 Bifidobacterium sp. 664 Bifidobacterium sp. 665 Bifidobacterium sp. 666 Bifidobacterium sp. 667 Bifidobacterium sp. 668 Bifidobacterium thermophilum 669 Bifidobacterium urinalis 670 Bilophila wadsworthia 671 Bisgaard Taxon 672 Bisgaard Taxon 673 Bisgaard Taxon 674 Bisgaard Taxon 675 Blastomonas natatoria 676 Blautia coccoides 677 Blautia glucerasea 678 Blautia glucerasei 679 Blautia hansenii 680 Blautia hydrogenotrophica 681 Blautia luti 682 Blautia producta 683 Blautia schinkii 684 Blautia sp. 685 Blautia stercoris 686 Blautia wexlerae 687 Brachybacterium alimentarium 688 Brachybacterium conglomeratum 689 Brachybacterium tyrofermentans 690 Brachyspira aalborgi 691 Brachyspira pilosicoli 692 Brachyspira sp. 693 Brachyspira sp. 694 Brachyspira sp. 695 Brevibacillus agri 696 Brevibacillus brevis 697 Brevibacillus centrosporus 698 Brevibacillus choshinensis 699 Brevibacillus invocatus 700 Brevibacillus laterosporus 701 Brevibacillus parabrevis 702 Brevibacillus reuszeri 703 Brevibacillus sp. 704 Brevibacillus thermoruber 705 Brevibacterium aurantiacum 706 Brevi bacterium casei 707 Brevi bacterium epidermidis 708 Brevibacterium frigoritolerans 709 Brevibacterium linens 710 Brevibacterium mcbrellneri 711 Brevibacterium paucivorans 712 Brevibacterium sanguinis 713 Brevibacterium sp. 714 Brevibacterium sp. 715 Brevundimonas subvibrioides 716 Bryantella formatexigens 717 Buchnera aphidicola 718 Bulleidia extructa 719 Butyricicoccus pullicaecorum 720 Butyricimonas virosa 721 Butyrivibrio crossotus 722 Butyrivibrio fibrisolvens 723 Caldimonas manganoxidans 724 Caminicella sporogenes 725 Candidatus arthromitus 726 Candidatus sulcia 727 Capnocytophaga canimorsus 728 Capnocytophaga genomo sp. 729 Capnocytophaga gingivalis 730 Capnocytophaga granulosa 731 Capnocytophaga ochracea 732 Capnocytophaga sp. 733 Capnocytophaga sp. 734 Capnocytophaga sp. 735 Capnocytophaga sp. 736 Capnocytophaga sp. 737 Capnocytophaga sp. 738 Capnocytophaga sp. 739 Capnocytophaga sputigena 740 Cardiobacterium hominis 741 Cardiobacterium valvarum 742 Carnobacterium divergens 743 Carnobacterium maltaromaticum 744 Catabacter hongkongensis 745 Catenibacterium mitsuokai 746 Catonella genomo sp. 747 Catonella morbi 748 Catonella sp. 749 Cedecea davisae 750 Cellulosimicrobium funkei 751 Cetobacterium somerae 752 Chlamydiales bacterium 753 Chlamydiales bacterium 754 Chlamydiales bacterium 755 Chloroflexi genomo sp. 756 Christensenella minuta 757 Chromobacterium violaceum 758 Chryseobacterium anthropi 759 Chryseobacterium gleum 760 Chryseobacterium hominis 761 Citrobacter amalonaticus 762 Citrobacter braakii 763 Citrobacter farmeri 764 Citrobacter freundii 765 Citrobacter gillenii 766 Citrobacter koseri 767 Citrobacter murliniae 768 Citrobacter rodentium 769 Citrobacter sedlakii 770 Citrobacter sp. 771 Citrobacter sp. 772 Citrobacter werkmanii 773 Citrobacter youngae 774 Cloacibacillus evryensis 775 Clostridiaceae bacterium 776 Clostridiaceae bacterium 777 Clostridiales bacterium 778 Clostridiales bacterium 779 Clostridiales bacterium 780 Clostridiales bacterium 781 Clostridiales bacterium 782 Clostridiales bacterium 783 Clostridiales bacterium 784 Clostridiales bacterium 785 Clostridiales genomo sp. 786 Clostridiales sp. 787 Clostridiales sp. 788 Clostridiales sp. 789 Clostridium acetobutylicum 790 Clostridium aerotolerans 791 Clostridium aldenense 792 Clostridium aldrichii 793 Clostridium algidicarnis 794 Clostridium algidixylanolyticum 795 Clostridium aminovalericum 796 Clostridium amygdalinum 797 Clostridium argentinense 798 Clostridium asparagiforme 799 Clostridium baratii 800 Clostridium bartlettii 801 Clostridium beijerinckii 802 Clostridium bifermentans 803 Clostridium bolteae 804 Clostridium butyricum 805 Clostridium cadaveris 806 Clostridium carboxidivorans 807 Clostridium carnis 808 Clostridium celatum 809 Clostridium celerecrescens 810 Clostridium cellulosi 811 Clostridium chauvoei 812 Clostridium citroniae 813 Clostridium clariflavum 814 Clostridium clostridioforme 815 Clostridium coccoides 816 Clostridium cochlearium 817 Clostridium cocleatum 818 Clostridium colicanis 819 Clostridium colinum 820 Clostridium disporicum 821 Clostridium estertheticum 822 Clostridium falla 823 Clostridium favososporum 824 Clostridium felsineum 825 Clostridium frigidicarnis 826 Clostridium gasigenes 827 Clostridium ghonii 828 Clostridium glycolicum 829 Clostridium glycyrrhizinilyticum 830 Clostridium haemolyticum 831 Clostridium hathewayi 832 Clostridium hiranonis 833 Clostridium histolyticum 834 Clostridium hylemonae 835 Clostridium indolis 836 Clostridium innocuum 837 Clostridium irregulare 838 Clostridium isatidis 839 Clostridium kluyveri 840 Clostridium lactatifermentans 841 Clostridium lavalense 842 Clostridium leptum 843 Clostridium limosum 844 Clostridium magnum 845 Clostridium malenominatum 846 Clostridium mayombei 847 Clostridium methylpentosum 848 Clostridium nexile 849 Clostridium novyi 850 Clostridium orbiscindens 851 Clostridium oroticum 852 Clostridium paraputrificum 853 Clostridium phytofermentans 854 Clostridium piliforme 855 Clostridium putrefaciens 856 Clostridium quinii 857 Clostridium ramosum 858 Clostridium rectum 859 Clostridium saccharogumia 860 Clostridium saccharolyticum 861 Clostridium saccharolyticum 862 Clostridium sardiniense 863 Clostridium sartagoforme 864 Clostridium scindens 865 Clostridium septicum 866 Clostridium sordellii 867 Clostridium sp. 868 Clostridium sp. 869 Clostridium sp. 870 Clostridium sp. 871 Clostridium sp. 872 Clostridium sp. 873 Clostridium sp. 874 Clostridium sp. 875 Clostridium sp. 876 Clostridium sp. 877 Clostridium sp. 878 Clostridium sp. 879 Clostridium sp. 880 Clostridium sp. 881 Clostridium sp. 882 Clostridium sp. 883 Clostridium sp. 884 Clostridium sphenoides 885 Clostridium spiroforme 886 Clostridium sporogenes 887 Clostridium sporosphaeroides 888 Clostridium stercorarium 889 Clostridium sticklandii 890 Clostridium straminisolvens 891 Clostridium subterminale 892 Clostridium sulfidigenes 893 Clostridium symbiosum 894 Clostridium tertium 895 Clostridium tetani 896 Clostridium thermocellum 897 Clostridium tyrobutyricum 898 Clostridium viride 899 Clostridium xylanolyticum 900 Collinsella aerofaciens 901 Collinsella intestinalis 902 Collinsella stercoris 903 Collinsella tanakaei 904 Comamonadaceae bacterium 905 Comamonadaceae bacterium 906 Comamonadaceae bacterium 907 Comamonadaceae bacterium 908 Comamonadaceae bacterium 909 Comamonas sp. 910 Conchiformibius kuhniae 911 Coprobacillus cateniformis 912 Coprobacillus sp. 913 Coprobacillus sp. 914 Coprococcus catus 915 Coprococcus comes 916 Coprococcus eutactus 917 Coprococcus sp. 918 Coriobacteriaceae bacterium 919 Coriobacteriaceae bacterium 920 Coriobacteriaceae bacterium 921 Corynebacterium accolens 922 Corynebacterium ammoniagenes 923 Corynebacterium appendicis 924 Corynebacterium argentoratense 925 Corynebacterium atypicum 926 Corynebacterium aurimucosum 927 Corynebacterium bovis 928 Corynebacterium canis 929 Corynebacterium casei 930 Corynebacterium confusum 931 Corynebacterium coyleae 932 Corynebacterium durum 933 Corynebacterium efficiens 934 Corynebacterium falsenii 935 Corynebacterium flavescens 936 Corynebacterium genitalium 937 Corynebacterium glaucum 938 Corynebacterium glucuronolyticum 939 Corynebacterium glutamicum 940 Corynebacterium hansenii 941 Corynebacterium imitans 942 Corynebacterium kroppenstedtii 943 Corynebacterium lipophiloflavum 944 Corynebacterium macginleyi 945 Corynebacterium mastitidis 946 Corynebacterium matruchotii 947 Corynebacterium minutissimum 948 Corynebacterium mucifaciens 949 Corynebacterium propinquum 950 Corynebacterium pseudodiphtheriticum 951 Corynebacterium pseudogenitalium 952 Corynebacterium pseudotuberculosis 953 Corynebacterium pyruviciproducens 954 Corynebacterium renale 955 Corynebacterium resistens 956 Corynebacterium riegelii 957 Corynebacterium simulans 958 Corynebacterium singulare 959 Corynebacterium sp. 960 Corynebacterium sp. 961 Corynebacterium sp. 962 Corynebacterium sp. 963 Corynebacterium sp. 964 Corynebacterium sundsvallense 965 Corynebacterium tuberculostearicum 966 Corynebacterium tuscaniae 967 Corynebacterium ulcerans 968 Corynebacterium ureicelerivorans 969 Corynebacterium variabile 970 Cronobacter malonaticus 971 Cronobacter sakazakii 972 Cronobacter turicensis 973 Cryptobacterium curtum 974 Cupriavidus metallidurans 975 Cytophaga xylanolytica 976 Deferribacteres sp. 977 Deferribacteres sp. 978 Deferribacteres sp. 979 Deinococcus radiodurans 980 Deinococcus sp. 981 Delftia acidovorans 982 Dermabacter hominis 983 Dermacoccus sp. 984 Desmospora activa 985 Desmospora sp. 986 Desulfitobacterium frappieri 987 Desulfitobacterium hafniense 988 Desulfobulbus sp. 989 Desulfotomaculum nigrificans 990 Desulfovibrio desulfuricans 991 Desulfovibrio fairfieldensis 992 Desulfovibrio piger 993 Desulfovibrio sp. 994 Desulfovibrio vulgaris 995 Dialister invisus 996 Dialister micraerophilus 997 Dialister microaerophilus 998 Dialister pneumosintes 999 Dialister propionicifaciens 1000 Dialister sp. 1001 Dialister succinatiphilus 1002 Dietzia natronolimnaea 1003 Dietzia sp. 1004 Dietzia sp. 1005 Dietzia timorensis 1006 Dorea formicigenerans 1007 Dorea longicatena 1008 Dysgonomonas gadei 1009 Dysgonomonas mossii 1010 Edwardsiella tarda 1011 Eggerthella lenta 1012 Eggerthella sinensis 1013 Eggerthella sp. 1014 Eggerthella sp. 1015 Eggerthella sp. 1016 Eikenella corrodens 1017 Enhydrobacter aerosaccus 1018 Enterobacter aerogenes 1019 Enterobacter asburiae 1020 Enterobacter cancerogenus 1021 Enterobacter cloacae 1022 Enterobacter cowanii 1023 Enterobacter hormaechei 1024 Enterobacter sp. 1025 Enterobacter sp. 1026 Enterobacter sp. 1027 Enterobacter sp. 1028 Enterobacter sp. 1029 Enterobacteriaceae bacterium 1030 Enterobacteriaceae bacterium 1031 Enterobacteriaceae bacterium 1032 Enterococcus avium 1033 Enterococcus caccae 1034 Enterococcus casseliflavus 1035 Enterococcus durans 1036 Enterococcus faecalis 1037 Enterococcus faecium 1038 Enterococcus gallinarum 1039 Enterococcus gilvus 1040 Enterococcus hawaiiensis 1041 Enterococcus hirae 1042 Enterococcus italicus 1043 Enterococcus mundtii 1044 Enterococcus raffinosus 1045 Enterococcus sp. 1046 Enterococcus sp. 1047 Enterococcus sp. 1048 Enterococcus sp. 1049 Enterococcus thailandicus 1050 Eremococcus coleocola 1051 Erysipelothrix inopinata 1052 Erysipelothrix rhusiopathiae 1053 Erysipelothrix tonsillarum 1054 Erysipelotrichaceae bacterium 1055 Erysipelotrichaceae bacterium 1056 Escherichia albertii 1057 Escherichia coli 1058 Escherichia fergusonii 1059 Escherichia hermannii 1060 Escherichia sp. 1061 Escherichia sp. 1062 Escherichia sp. 1063 Escherichia vulneris 1064 Ethanoligenens harbinense 1065 Eubacteriaceae bacterium 1066 Eubacterium barkeri 1067 Eubacterium biforme 1068 Eubacterium brachy 1069 Eubacterium budayi 1070 Eubacterium callanderi 1071 Eubacterium cellulosolvens 1072 Eubacterium contortum 1073 Eubacterium coprostanoligenes 1074 Eubacterium cylindroides 1075 Eubacterium desmolans 1076 Eubacterium dolichum 1077 Eubacterium eligens 1078 Eubacterium fissicatena 1079 Eubacterium hadrum 1080 Eubacterium hallii 1081 Eubacterium infirmum 1082 Eubacterium limosum 1083 Eubacterium moniliforme 1084 Eubacterium multiforme 1085 Eubacterium nitritogenes 1086 Eubacterium nodatum 1087 Eubacterium ramulus 1088 Eubacterium rectale 1089 Eubacterium ruminantium 1090 Eubacterium saburreum 1091 Eubacterium saphenum 1092 Eubacterium siraeum 1093 Eubacterium sp. 1094 Eubacterium sp. 1095 Eubacterium sp. 1096 Eubacterium sp. 1097 Eubacterium sp. 1098 Eubacterium sp. 1099 Eubacterium sp. 1100 Eubacterium sp. 1101 Eubacterium sp. 1102 Eubacterium sp. 1103 Eubacterium sp. 1104 Eubacterium tenue 1105 Eubacterium tortuosum 1106 Eubacterium ventriosum 1107 Eubacterium xylanophilum 1108 Eubacterium yurii 1109 Ewingella americana 1110 Exiguobacterium acetylicum 1111 Facklamia hominis 1112 Faecalibacterium prausnitzii 1113 Filifactor alocis 1114 Filifactor villosus 1115 Finegoldia magna 1116 Flavobacteriaceae genomo sp. 1117 Flavobacterium sp. 1118 Flavonifractor plautii 1119 Flexispira rappini 1120 Flexistipes sinusarabici 1121 Francisella novicida 1122 Francisella philomiragia 1123 Fulvimonas sp. 1124 Fusobacterium canifelinum 1125 Fusobacterium genomo sp. 1126 Fusobacterium genomo sp. 1127 Fusobacterium gonidiaformans 1128 Fusobacterium mortiferum 1129 Fusobacterium naviforme 1130 Fusobacterium necrogenes 1131 Fusobacterium necrophorum 1132 Fusobacterium nucleatum 1133 Fusobacterium periodonticum 1134 Fusobacterium russii 1135 Fusobacterium sp. 1136 Fusobacterium sp. 1137 Fusobacterium sp. 1138 Fusobacterium sp. 1139 Fusobacterium sp. 1140 Fusobacterium sp. 1141 Fusobacterium sp. 1142 Fusobacterium sp. 1143 Fusobacterium sp. 1144 Fusobacterium sp. 1145 Fusobacterium sp. 1146 Fusobacterium sp. 1147 Fusobacterium sp. 1148 Fusobacterium sp. 1149 Fusobacterium sp. 1150 Fusobacterium sp. 1151 Fusobacterium sp. 1152 Fusobacterium ulcerans 1153 Fusobacterium varium 1154 Gardnerella vaginalis 1155 Gemella haemolysans 1156 Gemella morbillorum 1157 Gemella morbillorum 1158 Gemella sanguinis 1159 Gemella sp. 1160 Gemella sp. 1161 Gemella sp. 1162 Gemella sp. 1163 Gemmiger formicilis 1164 Geobacillus kaustophilus 1165 Geobacillus sp. 1166 Geobacillus sp. 1167 Geobacillus stearothermophilus 1168 Geobacillus thermocatenulatus 1169 Geobacillus thermodenitrificans 1170 Geobacillus thermoglucosidasius 1171 Geobacillus thermoleovorans 1172 Geobacter bemidjiensis 1173 Gloeobacter violaceus 1174 Gluconacetobacter azotocaptans 1175 Gluconacetobactercdiazotrophicus 1176 Gluconacetobacter entanii 1177 Gluconacetobacter europaeus 1178 Gluconacetobacter hansenii 1179 Gluconacetobacter johannae 1180 Gluconacetobacter oboediens 1181 Gluconacetobacter xylinus 1182 Gordonia bronchialis 1183 Gordonia polyisoprenivorans 1184 Gordonia sp. 1185 Gordonia sputi 1186 Gordonia terrae 1187 Gordonibacter pamelaeae 1188 Gordonibacter pamelaeae 1189 Gracilibacter thermotolerans 1190 Gramella forsetii 1191 Granulicatella adiacens 1192 Granulicatella elegans 1193 Granulicatella paradiacens 1194 Granulicatella sp. 1195 Granulicatella sp. 1196 Granulicatella sp. 1197 Granulicatella sp. 1198 Granulicatella sp. 1199 Grimontia hollisae 1200 Haematobacter sp. 1201 Haemophilus aegyptius 1202 Haemophilus genomo sp. 1203 Haemophilus genomo sp. 1204 Haemophilus haemolyticus 1205 Haemophilus parahaemolyticus 1206 Haemophilus parainfluenzae 1207 Haemophilus paraphrophaemolyticus 1208 Haemophilus parasuis 1209 Haemophilus somnus 1210 Haemophilus sp. 1211 Haemophilus sp. 1212 Haemophilus sp. 1213 Haemophilus sp. 1214 Haemophilus sp. 1215 Haemophilus sp. 1216 Haemophilus sp. 1217 Haemophilus sp. 1218 Haemophilus sputorum 1219 Hafnia alvei 1220 Halomonas elongata 1221 Halomonas johnsoniae 1222 Halorubrum lipolyticum 1223 Helicobacter bilis 1224 Helicobacter canadensis 1225 Helicobacter cinaedi 1226 Helicobacter pullorum 1227 Helicobacter sp. 1228 Helicobacter winghamensis 1229 Heliobacterium modesticaldum 1230 Herbaspirillum seropedicae 1231 Herbaspirillum sp. 1232 Histophilus somni 1233 Holdemania filiformis 1234 Hydrogenoanaerobacterium saccharovorans 1235 Hyperthermus butylicus 1236 Hyphomicrobium sulfonivorans 1237 Hyphomonas neptunium 1238 Ignatzschineria indica 1239 Ignatzschineria sp. 1240 Ignicoccus islandicus 1241 Inquilinus limosus 1242 Janibacter limosus 1243 Janibacter melonis 1244 Janthinobacterium sp. 1245 Johnsonella ignava 1246 Jonquetella anthropi 1247 Kerstersia gyiorum 1248 Kingella denitrificans 1249 Kingella genomo sp. 1250 Kingella kingae 1251 Kingella oralis 1252 Kingella sp. 1253 Klebsiella sp. 1254 Klebsiella sp. 1255 Klebsiella sp. 1256 Klebsiella sp. 1257 Klebsiella sp. 1258 Klebsiella sp. 1259 Klebsiella sp. 1260 Klebsiella sp. 1261 Klebsiella sp. 1262 Klebsiella sp. 1263 Klebsiella sp. 1264 Klebsiella variicola 1265 Kluyvera ascorbata 1266 Kluyvera cryocrescens 1267 Kocuria marina 1268 Kocuria palustris 1269 Kocuria rhizophila 1270 Kocuria rosea 1271 Kocuria varians 1272 Lachnobacterium bovis 1273 Lachnospira multipara 1274 Lachnospira pectinoschiza 1275 Lachnospiraceae bacterium 1276 Lachnospiraceae bacterium 1277 Lachnospiraceae bacterium 1278 Lachnospiraceae bacterium 1279 Lachnospiraceae bacterium 1280 Lachnospiraceae bacterium 1281 Lachnospiraceae bacterium 1282 Lachnospiraceae bacterium 1283 Lachnospiraceae bacterium 1284 Lachnospiraceae bacterium 1285 Lachnospiraceae bacterium 1286 Lachnospiraceae bacterium 1287 Lachnospiraceae bacterium 1288 Lachnospiraceae bacterium 1289 Lachnospiraceae bacterium 1290 Lachnospiraceae bacterium 1291 Lachnospiraceae bacterium 1292 Lachnospiraceae genomo sp. 1293 Lactobacillus acidipiscis 1294 Lactobacillus acidophilus 1295 Lactobacillus alimentarius 1296 Lactobacillus amylolyticus 1297 Lactobacillus amylovorus 1298 Lactobacillus antri 1299 Lactobacillus brevis 1300 Lactobacillus buchneri 1301 Lactobacillus casei 1302 Lactobacillus catenaformis 1303 Lactobacillus coleohominis 1304 Lactobacillus coryniformis 1305 Lactobacillus crispatus 1306 Lactobacillus curvatus 1307 Lactobacillus delbrueckii 1308 Lactobacillus dextrinicus 1309 Lactobacillus farciminis 1310 Lactobacillus fermentum 1311 Lactobacillus gasseri 1312 Lactobacillus gastricus 1313 Lactobacillus genomo sp. 1314 Lactobacillus genomo sp. 1315 Lactobacillus helveticus 1316 Lactobacillus hilgardii 1317 Lactobacillus hominis 1318 Lactobacillus iners 1319 Lactobacillus jensenii 1320 Lactobacillus johnsonii 1321 Lactobacillus kalixensis 1322 Lactobacillus kefiranofaciens 1323 Lactobacillus kefiri 1324 Lactobacillus kimchii 1325 Lactobacillus leichmannii 1326 Lactobacillus mucosae 1327 Lactobacillus murinus 1328 Lactobacillus nodensis 1329 Lactobacillus oeni 1330 Lactobacillus oris 1331 Lactobacillus parabrevis 1332 Lactobacillus parabuchneri 1333 Lactobacillus paracasei 1334 Lactobacillus parakefiri 1335 Lactobacillus pentosus 1336 Lactobacillus perolens 1337 Lactobacillus plantarum 1338 Lactobacillus pontis 1339 Lactobacillus reuteri 1340 Lactobacillus rhamnosus 1341 Lactobacillus rogosae 1342 Lactobacillus ruminis 1343 Lactobacillus sakei 1344 Lactobacillus salivarius 1345 Lactobacillus saniviri 1346 Lactobacillus senioris 1347 Lactobacillus sp. 1348 Lactobacillus sp. 1349 Lactobacillus sp. 1350 Lactobacillus sp. 1351 Lactobacillus sp. 1352 Lactobacillus sp. 1353 Lactobacillus sp. 1354 Lactobacillus sp. 1355 Lactobacillus sp. 1356 Lactobacillus sp. 1357 Lactobacillus sp. 1358 Lactobacillus sp. 1359 Lactobacillus sp. 1360 Lactobacillus sp. 1361 Lactobacillus sp. 1362 Lactobacillus sp. 1363 Lactobacillus sp. 1364 Lactobacillus sp. 1365 Lactobacillus tucceti 1366 Lactobacillus ultunensis 1367 Lactobacillus vaginalis 1368 Lactobacillus vini 1369 Lactobacillus vitulinus 1370 Lactobacillus zeae 1371 Lactococcus garvieae 1372 Lactococcus lactis 1373 Lactococcus raffinolactis 1374 Lactonifactor longoviformis 1375 Laribacter hongkongensis 1376 Lautropia mirabilis 1377 Lautropia sp. 1378 Leminorella grimontii 1379 Leminorella richardii 1380 Leptotrichia buccalis 1381 Leptotrichia genomo sp. 1382 Leptotrichia goodfellowii 1383 Leptotrichia hofstadii 1384 Leptotrichia shahii 1385 Leptotrichia sp. 1386 Leptotrichia sp. 1387 Leptotrichia sp. 1388 Leptotrichia sp. 1389 Leptotrichia sp. 1390 Leptotrichia sp. 1391 Leptotrichia sp. 1392 Leuconostoc carnosum 1393 Leuconostoc citreum 1394 Leuconostoc gasicomitatum 1395 Leuconostoc inhae 1396 Leuconostoc kimchii 1397 Leuconostoc lactis 1398 Leuconostoc mesenteroides 1399 Leuconostoc pseudomesenteroides 1400 Listeria innocua 1401 Listeria ivanovii 1402 Luteococcus sanguinis 1403 Lutispora thermophila 1404 Lysinibacillus fusiformis 1405 Lysinibacillus sphaericus 1406 Macrococcus caseolyticus 1407 Mannheimia haemolytica 1408 Marvinbryantia formatexigens 1409 Massilia sp. 1410 Megamonas funiformis 1411 Megamonas hypermegale 1412 Megasphaera genomo sp. 1413 Megasphaera genomo sp. 1414 Megasphaera micronuciformis 1415 Megasphaera sp. 1416 Megasphaera sp. 1417 Metallosphaera sedula 1418 Methanobacterium formicicum 1419 Methanobrevibacter acididurans 1420 Methanobrevibacter arboriphilus 1421 Methanobrevibacter curvatus 1422 Methanobrevibacter cuticularis 1423 Methanobrevibacter filiformis 1424 Methanobrevibacter gottschalkii 1425 Methanobrevibacter millerae 1426 Methanobrevibacter olleyae 1427 Methanobrevibacter orails 1428 Methanobrevibacter ruminantium 1429 Methanobrevibacter smithii 1430 Methanobrevibacter thaueri 1431 Methanobrevibacter woesei 1432 Methanobrevibacter wolinii 1433 Methanosphaera stadtmanae 1434 Methylobacterium extorquens 1435 Methylobacterium podarium 1436 Methylobacterium radiotolerans 1437 Methylobacterium sp. 1438 Methylobacterium sp. 1439 Methylocella silvestris 1440 Methylophilus sp. 1441 Microbacterium chocolatum 1442 Microbacterium flavescens 1443 Microbacterium gubbeenense 1444 Microbacterium lacticum 1445 Microbacterium oleivorans 1446 Microbacterium oxydans 1447 Microbacterium paraoxydans 1448 Microbacterium phyllosphaerae 1449 Microbacterium schleiferi 1450 Microbacterium sp. 1451 Microbacterium sp. 1452 Microbacterium testaceum 1453 Micrococcus antarcticus 1454 Micrococcus luteus 1455 Micrococcus lylae 1456 Micrococcus sp. 1457 Microcystis aeruginosa 1458 Mitsuokella jalaludinii 1459 Mitsuokella multacida 1460 Mitsuokella sp. 1461 Mitsuokella sp. 1462 Mobiluncus curtisii 1463 Mobiluncus mulieris 1464 Moellerella wisconsensis 1465 Mogibacterium diversum 1466 Mogibacterium neglectum 1467 Mogibacterium pumilum 1468 Mogibacterium timidum 1469 Mollicutes bacterium 1470 Moorella thermoacetica 1471 Moraxella catarrhalis 1472 Moraxella lincolnii 1473 Moraxella osloensis 1474 Moraxella sp. 1475 Moraxella sp. 1476 Morganella morganii 1477 Morganella sp. 1478 Morococcus cerebrosus 1479 Moryella indoligenes 1480 Mycobacterium sp. 1481 Mycobacterium sp. 1482 Mycobacterium sp. 1483 Mycobacterium sp. 1484 Mycobacterium sp. 1485 Mycobacterium sp. 1486 Mycobacterium sp. 1487 Mycobacterium sp. 1488 Mycobacterium sp. 1489 Mycobacterium sp. 1490 Mycobacterium sp. 1491 Mycobacterium sp. 1492 Mycobacterium sp. 1493 Mycobacterium sp. 1494 Mycobacterium sp. 1495 Mycoplasma agalactiae 1496 Mycoplasma amphoriforme 1497 Mycoplasma arthritidis 1498 Mycoplasma bovoculi 1499 Mycoplasma faucium 1500 Mycoplasma fermentans 1501 Mycoplasma flocculare 1502 Mycoplasma genitalium 1503 Mycoplasma hominis 1504 Mycoplasma orale 1505 Mycoplasma ovipneumoniae 1506 Mycoplasma penetrans 1507 Mycoplasma pneumoniae 1508 Mycoplasma putrefaciens 1509 Mycoplasma salivarium 1510 Mycoplasmataceae genomo sp. 1511 Myroides odoratimimus 1512 Myroides sp. 1513 Neisseria bacilliformis 1514 Neisseria cinerea 1515 Neisseria elongata 1516 Neisseria flavescens 1517 Neisseria genomo sp. 1518 Neisseria lactamica 1519 Neisseria macacae 1520 Neisseria mucosa 1521 Neisseria pharyngis 1522 Neisseria polysaccharea 1523 Neisseria sicca 1524 Neisseria sp. 1525 Neisseria sp. 1526 Neisseria sp. 1527 Neisseria sp. 1528 Neisseria sp. 1529 Neisseria sp. 1530 Neisseria sp. 1531 Neisseria subflava 1532 Neorickettsia risticii 1533 Neorickettsia sennetsu 1534 Nocardia brasiliensis 1535 Nocardia cyriacigeorgica 1536 Nocardia farcinica 1537 Nocardia purls 1538 Nocardia sp. 1539 Nocardiopsis dassonvillei 1540 Novosphingobium aromaticivorans 1541 Oceanobacillus caeni 1542 Oceanobacillus sp. 1543 Ochrobactrum anthropi 1544 Ochrobactrum intermedium 1545 Ochrobactrum pseudintermedium 1546 Odoribacter laneus 1547 Odoribacter splanchnicus 1548 Okadaella gastrococcus 1549 Oligella ureolytica 1550 Oligella urethralis 1551 Olsenella genomo sp. 1552 Olsenella profusa 1553 Olsenella sp. 1554 Olsenella sp. 1555 Olsenella uli 1556 Opitutus terrae 1557 Oribacterium sinus 1558 Oribacterium sp. 1559 Oribacterium sp. 1560 Oribacterium sp. 1561 Oribacterium sp. 1562 Oribacterium sp. 1563 Oribacterium sp. 1564 Oribacterium sp. 1565 Oribacterium sp. 1566 Ornithinibacillus bavariensis 1567 Ornithinibacillus sp. 1568 Oscillibacter sp. 1569 Oscillibacter valericigenes 1570 Oscillospira guilliermondii 1571 Oxalobacter formigenes 1572 Paenibacillus barcinonensis 1573 Paenibacillus barengoltzii 1574 Paenibacillus chibensis 1575 Paenibacillus cookii 1576 Paenibacillus durus 1577 Paenibacillus glucanolyticus 1578 Paenibacillus lactis 1579 Paenibacillus lautus 1580 Paenibacillus pabuli 1581 Paenibacillus polymyxa 1582 Paenibacillus popilliae 1583 Paenibacillus sp. 1584 Paenibacillus sp. 1585 Paenibacillus sp. 1586 Paenibacillus sp. 1587 Paenibacillus sp. 1588 Paenibacillus sp. 1589 Paenibacillus sp. 1590 Paenibacillus timonensis 1591 Pantoea agglomerans 1592 Pantoea ananatis 1593 Pantoea brenneri 1594 Pantoea citrea 1595 Pantoea conspicua 1596 Pantoea septica 1597 Papillibacter cinnamivorans 1598 Parabacteroides distasonis 1599 Parabacteroides goldsteinii 1600 Parabacteroides gordonii 1601 Parabacteroides johnsonii 1602 Parabacteroides merdae 1603 Parabacteroides sp. 1604 Parabacteroides sp. 1605 Parachlamydia sp. 1606 Paracoccus denitrificans 1607 Paracoccus marcusii 1608 Paraprevotella clara 1609 Paraprevotella xylaniphila 1610 Parascardovia denticolens 1611 Parasutterella excrementihominis 1612 Parasutterella secunda 1613 Parvimonas micra 1614 Parvimonas sp. 1615 Pasteurella bettyae 1616 Pasteurella dagmatis 1617 Pasteurella multocida 1618 Pediococcus acidilactici 1619 Pediococcus pentosaceus 1620 Peptococcus niger 1621 Peptococcus sp. 1622 Peptococcus sp. 1623 Peptoniphilus asaccharolyticus 1624 Peptoniphilus duerdenii 1625 Peptoniphilus harei 1626 Peptoniphilus indolicus 1627 Peptoniphilus ivorii 1628 Peptoniphilus lacrimalis 1629 Peptoniphilus sp. 1630 Peptoniphilus sp. 1631 Peptoniphilus sp. 1632 Peptoniphilus sp. 1633 Peptoniphilus sp. 1634 Peptoniphilus sp. 1635 Peptoniphilus sp. 1636 Peptostreptococcaceae bacterium 1637 Peptostreptococcus anaerobius 1638 Peptostreptococcus micros 1639 Peptostreptococcus sp. 1640 Peptostreptococcus sp. 1641 Peptostreptococcus sp. 1642 Peptostreptococcus sp. 1643 Peptostreptococcus stomatis 1644 Phascolarctobacterium faecium 1645 Phascolarctobacterium sp. 1646 Phascolarctobacterium succinatutens 1647 Phenylobacterium zucineum 1648 Photorhabdus asymbiotica 1649 Pigmentiphaga daeguensis 1650 Planomicrobium koreense 1651 Plesiomonas shigelloides 1652 Porphyromonadaceae bacterium 1653 Porphyromonas asaccharolytica 1654 Porphyromonas endodontalis 1655 Porphyromonas gingivalis 1656 Porphyromonas levii 1657 Porphyromonas macacae 1658 Porphyromonas somerae 1659 Porphyromonas sp. 1660 Porphyromonas sp. 1661 Porphyromonas sp. 1662 Porphyromonas sp. 1663 Porphyromonas sp. 1664 Porphyromonas uenonis 1665 Prevotella albensis 1666 Prevotella amnii 1667 Prevotella bergensis 1668 Prevotella bivia 1669 Prevotella brevis 1670 Prevotella buccae 1671 Prevotella buccalis 1672 Prevotella copri 1673 Prevotella corporis 1674 Prevotella dentalis 1675 Prevotella denticola 1676 Prevotella disiens 1677 Prevotella genomo sp. 1678 Prevotella genomo sp. 1679 Prevotella genomo sp. 1680 Prevotella genomo sp. 1681 Prevotella genomo sp. 1682 Prevotella heparinolytica 1683 Prevotella histicola 1684 Prevotella intermedia 1685 Prevotella loescheii 1686 Prevotella maculosa 1687 Prevotella marshii 1688 Prevotella melaninogenica 1689 Prevotella micans 1690 Prevotella multiformis 1691 Prevotella multisaccharivora 1692 Prevotella nanceiensis 1693 Prevotella nigrescens 1694 Prevotella oralis 1695 Prevotella oris 1696 Prevotella oulorum 1697 Prevotella pallens 1698 Prevotella ruminicola 1699 Prevotella salivae 1700 Prevotella sp. 1701 Prevotella sp. 1702 Prevotella sp. 1703 Prevotella sp. 1704 Prevotella sp. 1705 Prevotella sp. 1706 Prevotella sp. 1707 Prevotella sp. 1708 Prevotella sp. 1709 Prevotella sp. 1710 Prevotella sp. 1711 Prevotella sp. 1712 Prevotella sp. 1713 Prevotella sp. 1714 Prevotella sp. 1715 Prevotella sp. 1716 Prevotella sp. 1717 Prevotella sp. 1718 Prevotella sp. 1719 Prevotella sp. 1720 Prevotella sp. 1721 Prevotella sp. 1722 Prevotella sp. 1723 Prevotella sp. 1724 Prevotella sp. 1725 Prevotella sp. 1726 Prevotella sp. 1727 Prevotella sp. 1728 Prevotella sp. 1729 Prevotella sp. 1730 Prevotella sp. 1731 Prevotella sp. 1732 Prevotella sp. 1733 Prevotella sp. 1734 Prevotella sp. 1735 Prevotella sp. 1736 Prevotella sp. 1737 Prevotella sp. 1738 Prevotella sp. 1739 Prevotella sp. 1740 Prevotella sp. 1741 Prevotella sp. 1742 Prevotella sp. 1743 Prevotella sp. 1744 Prevotella sp. 1745 Prevotella sp. 1746 Prevotella stercorea 1747 Prevotella tannerae 1748 Prevotella timonensis 1749 Prevotella veroralis 1750 Prevotellaceae bacterium 1751 Prochlorococcus marinus 1752 Propionibacteriaceae bacterium 1753 Propionibacterium acidipropionici 1754 Propionibacterium acnes 1755 Propionibacterium avidum 1756 Propionibacterium freudenreichii 1757 Propionibacterium granulosum 1758 Propionibacterium jensenii 1759 Propionibacterium propionicum 1760 Propionibacterium sp. 1761 Propionibacterium sp. 1762 Propionibacterium sp. 1763 Propionibacterium sp. 1764 Propionibacterium sp. 1765 Propionibacterium thoenii 1766 Proteus mirabilis 1767 Proteus penneri 1768 Proteus sp. 1769 Proteus vulgaris 1770 Providencia alcalifaciens 1771 Providencia rettgeri 1772 Providencia rustigianii 1773 Providencia stuartii 1774 Pseudoclavibacter sp. 1775 Pseudoflavonifractor capillosus 1776 Pseudomonas aeruginosa 1777 Pseudomonas fluorescens 1778 Pseudomonas gessardii 1779 Pseudomonas mendocina 1780 Pseudomonas monteilii 1781 Pseudomonas poae 1782 Pseudomonas pseudoalcaligenes 1783 Pseudomonas putida 1784 Pseudomonas sp. 1785 Pseudomonas sp. 1786 Pseudomonas sp. 1787 Pseudomonas stutzeri 1788 Pseudomonas tolaasii 1789 Pseudomonas viridiflava 1790 Pseudoramibacter alactolyticus 1791 Psychrobacter arcticus 1792 Psychrobacter cibarius 1793 Psychrobacter cryohalolentis 1794 Psychrobacter faecalis 1795 Psychrobacter nivimaris 1796 Psychrobacter pulmonis 1797 Psychrobacter sp. 1798 Pyramidobacter piscolens 1799 Ralstonia pickettii 1800 Ralstonia sp. 1801 Raoultella ornithinolytica 1802 Raoultella planticola 1803 Raoultella terrigena 1804 Rhodobacter sp. 1805 Rhodobacter sphaeroides 1806 Rhodococcus corynebacterioides 1807 Rhodococcus equi 1808 Rhodococcus erythropolis 1809 Rhodococcus fascians 1810 Rhodopseudomonas palustris 1811 Robinsoniella peoriensis 1812 Roseburia cecicola 1813 Roseburia faecalis 1814 Roseburia faecis 1815 Roseburia hominis 1816 Roseburia intestinalis 1817 Roseburia inulinivorans 1818 Roseburia sp. 1819 Roseburia sp. 1820 Roseiflexus castenholzii 1821 Roseomonas cervicalis 1822 Roseomonas mucosa 1823 Roseomonas sp. 1824 Roseomonas sp. 1825 Roseomonas sp. 1826 Roseomonas sp. 1827 Rothia aeria 1828 Rothia dentocariosa 1829 Rothia mucilaginosa 1830 Rothia nasimurium 1831 Rothia sp. 1832 Ruminobacter amylophilus 1833 Ruminococcaceae bacterium 1834 Ruminococcus albus 1835 Ruminococcus bromii 1836 Ruminococcus callidus 1837 Ruminococcus champanellensis 1838 Ruminococcus flavefaciens 1839 Ruminococcus gnavus 1840 Ruminococcus hansenii 1841 Ruminococcus lactaris 1842 Ruminococcus obeum 1843 Ruminococcus sp. 1844 Ruminococcus sp. 1845 Ruminococcus sp. 1846 Ruminococcus sp. 1847 Ruminococcus sp. 1848 Ruminococcus torques 1849 Saccharomonospora viridis 1850 Sarcina ventriculi 1851 Scardovia inopinata 1852 Scardovia wiggsiae 1853 Segniliparus rotundus 1854 Segniliparus rugosus 1855 Selenomonas artemidis 1856 Selenomonas dianae 1857 Selenomonas flueggei 1858 Selenomonas genomo sp. 1859 Selenomonas genomo sp. 1860 Selenomonas genomo sp. 1861 Selenomonas genomo sp. 1862 Selenomonas genomo sp. 1863 Selenomonas genomo sp. 1864 Selenomonas infeli 1865 Selenomonas noxia 1866 Selenomonas ruminantium 1867 Selenomonas sp. 1868 Selenomonas sp. 1869 Selenomonas sp. 1870 Selenomonas sp. 1871 Selenomonas sp. 1872 Selenomonas sp. 1873 Selenomonas sp. 1874 Selenomonas sp. 1875 Selenomonas sp. 1876 Selenomonas sp. 1877 Selenomonas sp. 1878 Selenomonas sp. 1879 Selenomonas sp. 1880 Selenomonas sputigena 1881 Serratia fonticola 1882 Serratia liquefaciens 1883 Serratia marcescens 1884 Serratia odorifera 1885 Serratia proteamaculans 1886 Shewanella putrefaciens 1887 Shuttleworthia satelles 1888 Shuttleworthia sp. 1889 Shuttleworthia sp. 1890 Simonsiella muelleri 1891 Slackia equolifaciens 1892 Slackia exigua 1893 Slackia faecicanis 1894 Slackia heliotrinireducens 1895 Slackia isoflavoniconvertens 1896 Slackia piriformis 1897 Slackia sp. 1898 Solobacterium moorei 1899 Sphingobacterium faecium 1900 Sphingobacterium mizutaii 1901 Sphingobacterium multivorum 1902 Sphingobacterium spiritivorum 1903 Sphingomonas echinoides 1904 Sphingomonas sp. 1905 Sphingomonas sp. 1906 Sphingomonas sp. 1907 Sphingomonas sp. 1908 Sphingopyxis alaskensis 1909 Spiroplasma insolitum 1910 Sporobacter termitidis 1911 Sporolactobacillus inulinus 1912 Sporolactobacillus nakayamae 1913 Sporosarcina newyorkensis 1914 Sporosarcina sp. 1915 Staphylococcaceae bacterium 1916 Staphylococcus aureus 1917 Staphylococcus auricularis 1918 Staphylococcus capitis 1919 Staphylococcus caprae 1920 Staphylococcus carnosus 1921 Staphylococcus cohnii 1922 Staphylococcus condimenti 1923 Staphylococcus epidermidis 1924 Staphylococcus equorum 1925 Staphylococcus fleurettii 1926 Staphylococcus haemolyticus 1927 Staphylococcus hominis 1928 Staphylococcus lugdunensis 1929 Staphylococcus pasteuri 1930 Staphylococcus pseudintermedius 1931 Staphylococcus saccharolyticus 1932 Staphylococcus saprophyticus 1933 Staphylococcus sciuri 1934 Staphylococcus sp. 1935 Staphylococcus sp. 1936 Staphylococcus sp. 1937 Staphylococcus succinus 1938 Staphylococcus vitulinus 1939 Staphylococcus warneri 1940 Staphylococcus xylosus 1941 Stenotrophomonas maltophilia 1942 Stenotrophomonas sp. 1943 Streptobacillus moniliformis 1944 Streptococcus agalactiae 1945 Streptococcus alactolyticus 1946 Streptococcus anginosus 1947 Streptococcus australis 1948 Streptococcus bovis 1949 Streptococcus canis 1950 Streptococcus constellatus 1951 Streptococcus cristatus 1952 Streptococcus downei 1953 Streptococcus dysgalactiae 1954 Streptococcus equi 1955 Streptococcus equinus 1956 Streptococcus gallolyticus 1957 Streptococcus genomo sp. 1958 Streptococcus genomo sp. 1959 Streptococcus genomo sp. 1960 Streptococcus genomo sp. 1961 Streptococcus genomo sp. 1962 Streptococcus genomo sp. 1963 Streptococcus genomo sp. 1964 Streptococcus genomo sp. 1965 Streptococcus gordonii 1966 Streptococcus infantarius 1967 Streptococcus infantis 1968 Streptococcus intermedius 1969 Streptococcus lutetiensis 1970 Streptococcus massiliensis 1971 Streptococcus milleri 1972 Streptococcus mitis 1973 Streptococcus mutans 1974 Streptococcus oligofermentans 1975 Streptococcus oralis 1976 Streptococcus parasanguinis 1977 Streptococcus pasteurianus 1978 Streptococcus peroris 1979 Streptococcus pneumoniae 1980 Streptococcus porcinus 1981 Streptococcus pseudopneumoniae 1982 Streptococcus pseudoporcinus 1983 Streptococcus ratti 1984 Streptococcus salvarius 1985 Streptococcus sanguinis 1986 Streptococcus sinensis 1987 Streptococcus sp. 1988 Streptococcus sp. 1989 Streptococcus sp. 1990 Streptococcus sp. 1991 Streptococcus sp. 1992 Streptococcus sp. 1993 Streptococcus sp. 1994 Streptococcus sp. 1995 Streptococcus sp. 1996 Streptococcus sp. 1997 Streptococcus sp. 1998 Streptococcus sp. 1999 Streptococcus sp. 2000 Streptococcus sp. 2001 Streptococcus sp. 2002 Streptococcus sp. 2003 Streptococcus sp. 2004 Streptococcus sp. 2005 Streptococcus sp. 2006 Streptococcus sp. 2007 Streptococcus sp. 2008 Streptococcus sp. 2009 Streptococcus sp. 2010 Streptococcus sp. 2011 Streptococcus sp. 2012 Streptococcus sp. 2013 Streptococcus sp. 2014 Streptococcus sp. 2015 Streptococcus sp. 2016 Streptococcus sp. 2017 Streptococcus sp. 2018 Streptococcus sp. 2019 Streptococcus sp. 2020 Streptococcus sp. 2021 Streptococcus sp. 2022 Streptococcus sp. 2023 Streptococcus sp. 2024 Streptococcus sp. 2025 Streptococcus sp. 2026 Streptococcus sp. 2027 Streptococcus sp. 2028 Streptococcus sp. 2029 Streptococcus sp. 2030 Streptococcus sp. 2031 Streptococcus sp. 2032 Streptococcus sp. 2033 Streptococcus sp. 2034 Streptococcus sp. 2035 Streptococcus sp. 2036 Streptococcus sp. 2037 Streptococcus sp. 2038 Streptococcus sp. 2039 Streptococcus sp. 2040 Streptococcus suis 2041 Streptococcus thermophilus 2042 Streptococcus uberis 2043 Streptococcus urinalis 2044 Streptococcus vestibularis 2045 Streptococcus viridans 2046 Streptomyces albus 2047 Streptomyces griseus 2048 Streptomyces sp. 2049 Streptomyces sp. 2050 Streptomyces sp. 2051 Streptomyces sp. 2052 Streptomyces sp. 2053 Streptomyces thermoviolaceus 2054 Subdohgranulum variabile 2055 Succinatimonas hippei 2056 Sutterella morbirenis 2057 Sutterella parvirubra 2058 Sutterella sanguinus 2059 Sutterella sp. 2060 Sutterella stercoricanis 2061 Sutterella wadsworthensis 2062 Synergistes genomo sp. 2063 Synergistes sp. 2064 Synergistetes bacterium 2065 Synergistetes bacterium 2066 Synergistetes bacterium 2067 Synergistetes bacterium 2068 Synergistetes bacterium 2069 Syntrophococcus sucromutans 2070 Syntrophomonadaceae genomo sp. 2071 Tannerella forsythia 2072 Tannerella sp. 2073 Tatlockia micdadei 2074 Tatumella ptyseos 2075 Tessaracoccus sp. 2076 Tetragenococcus halophilus 2077 Tetragenococcus koreensis 2078 Thermoanaerobacter pseudethanolicus 2079 Thermobifida fusca 2080 Thermofilum pendens 2081 Thermus aquaticus 2082 Tissierella praeacuta 2083 Trabulsiella guamensis 2084 Treponema genomo sp. 2085 Treponema genomo sp. 2086 Treponema genomo sp. 2087 Treponema genomo sp. 2088 Treponema phagedenis 2089 Treponema sp. 2090 Treponema sp. 2091 Treponema sp. 2092 Treponema sp. 2093 Treponema sp. 2094 Treponema sp. 2095 Treponema sp. 2096 Treponema sp. 2097 Treponema sp. 2098 Treponema sp. 2099 Treponema sp. 2100 Treponema sp. 2101 Treponema sp. 2102 Treponema sp. 2103 Treponema sp. 2104 Treponema sp. 2105 Treponema sp. 2106 Treponema sp. 2107 Treponema sp. 2108 Treponema sp. 2109 Treponema sp. 2110 Treponema sp. 2111 Tropheryma whipplei 2112 Trueperella pyogenes 2113 Tsukamurella paurometabola 2114 Tsukamurella tyrosinosolvens 2115 Turicibacter sanguinis 2116 Ureaplasma parvum 2117 Ureaplasma urealyticum 2118 Ureibacillus composti 2119 Ureibacillus suwonensis 2120 Ureibacillus terrenus 2121 Ureibacillus thermophilus 2122 Ureibacillus thermosphaericus 2123 Vagococcus fluvialis 2124 Veillonella atypica 2125 Veillonella dispar 2126 Veillonella genomo sp. 2127 Veillonella montpellierensis 2128 Veillonella parvula 2129 Veillonella sp. 2130 Veillonella sp. 2131 Veillonella sp. 2132 Veillonella sp. 2133 Veillonella sp. 2134 Veillonella sp. 2135 Veillonella sp. 2136 Veillonella sp. 2137 Veillonella sp. 2138 Veillonella sp. 2139 Veillonella sp. 2140 Veillonella sp. 2141 Veillonella sp. 2142 Veillonella sp. 2143 Veillonella sp. 2144 Veillonellaceae bacterium 2145 Veillonellaceae bacterium 2146 Victivallaceae bacterium 2147 Victivallis vadensis 2148 Virgibacillus proomii 2149 Weissella beninensis 2150 Weissella cibaria 2151 Weissella confusa 2152 Weissella hellenica 2153 Weissella kandleri 2154 Weissella koreensis 2155 Weissella paramesenteroides 2156 Weissella sp. 2157 Wolinella succinogenes 2158 Xanthomonadaceae bacterium 2159 Xanthomonas campestris 2160 Xanthomonas sp. 2161 Xenophilus aerolatus 2162 Yokenella regensburgei 2163 Zimmermannella bifida 2164 Zymomonas mobilis 2165 Alistipes shahii 2166 Bacteroides caccae 2167 Bacteroides eggerthii 2168 Bacteroides sp. 2169 Bacteroides sp. 2170 Bacteroides sp. 2171 Bacteroides uniformis 2172 Bacteroides vulgatus 2173 Bacteroides vulgatus 2174 Bifidobacterium adolescentis 2175 Bifidobacterium pseudocatenulatum 2176 Blautia producta 2177 Blautia producta 2178 Blautia schinkii 2179 Clostridium bolteae 2180 Clostridium butyricum 2181 Clostridium disporicum 2182 Clostridium hathewayi 2183 Clostridium hylemonae 2184 Clostridium innocuum 2185 Clostridium innocuum 2186 Clostridium mayombei 2187 Clostridium nexile 2188 Clostridium orbiscindens 2189 Clostridium symbiosum 2190 Clostridium tertium 2191 Collinsella aerofaciens 2192 Coprobacillus sp. 2193 Coprococcus catus 2194 Coprococcus comes 2195 Dorea formicigenerans 2196 Dorea longicatena 2197 Enterococcus faecalis 2198 Erysipelotrichaceae bacterium 2199 Escherichia coli 2200 Escherichia coli 2201 Eubacterium eligens 2202 Eubacterium rectale 2203 Eubacterium rectale 2204 Faecalibacterium prausnitzii 2205 Faecalibacterium prausnitzii 2206 Lachnospiraceae bacterium 2207 Odoribacter splanchnicus 2208 Odoribacter splanchnicus 2209 Parabacteroides merdae 2210 Roseburia intestinalis 2211 Ruminococcus bromii 2212 Ruminococcus gnavus 2213 Ruminococcus obeum 2214 Ruminococcus torques 2215 Streptococcus thermophilus 2216 Escherichia coli 2217 Streptococcus thermophilus 2218 Escherichia coli 2219

Therapeutic Compositions

Any of the GABA-producing bacteria described herein (e.g., natural bacteria or engineered bacteria), or any combination thereof (including combinations of natural and engineered bacteria) can be incorporated into a therapeutic composition. For instance, the therapeutic compositions can be administered to a patient in need thereof to treat or alleviate the symptom of a mental illness or central nervous system disease.

Purification of Strains

In some embodiments, bacteria are purified prior to incorporation into a therapeutic composition. For instance, bacteria can be purified so that the population of bacteria is substantially free of other bacteria (e.g., contains at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, or at least 98%, at least 99% of the specific bacterial strain or strains desired in the composition).

In some embodiments, the therapeutic composition is a probiotic or a medical food comprising at least one GABA-producing bacterial strain. The strain can be administered, for instance, as a probiotic, as capsules, tablets, caplets, pills, troches, lozenges, powders, and/or granules. The strain can also be formulated as a medical food. The GABA-producing bacteria can also be administered as a fecal transplant or suppository.

In some embodiments, the dose of the therapeutic can contain 1×10⁴, 1×10⁵, 1×10⁶, 1×10⁷, 1×10⁸, 1×10⁹, 1×10¹⁰, 1×10¹¹ or greater than 1×10¹¹ colony forming units (CFUs) of the desired bacterial species. For instance, the desired bacterial species can be GABA-producing bacteria, bacteria that are capable of inhibiting the growth of GABA-consuming bacteria, or a combination thereof.

In some embodiments, the therapeutic composition or dose unit comprises a pharmaceutically acceptable formulation, including an enteric coating or similar to survive the acidity of the stomach and enabled delivery into the small or large intestines, prebiotics (such as, but not limited to, amino acids (including arginine, glutamate, and ornithine), biotin, fructooligosaccharide, galactooligosaccharides, hemicelluloses (e.g., arabinoxylan, xylan, xyloglucan, and glucomannan), inulin, chitin, lactulose, mannan oligosaccharides, oligofructose-enriched inulin, gums (e.g., guar gum, gum arabic and carregenaan), oligofructose, oligodextrose, tagatose, resistant maltodextrins (e.g., resistant starch), trans-galactooligosaccharide, pectins (e.g., xylogalactouronan, citrus pectin, apple pectin, and rhamnogalacturonan-I), dietary fibers (e.g., soy fiber, sugarbeet fiber, pea fiber, corn bran, and oat fiber) and xylooligosaccharides, polyamines (such as but not limited to spermidine and putrescine), an effective amount of an anti-bacterial agent, anti-fungal agent, anti-viral agent, or anti-parasitic agent, or any combinations of the above. For instance, the therapeutic composition can also be in the form of a yogurt containing one or more purified strains of GABA-producing bacteria.

Disease Indications

In one or more embodiments of any of the above-aspects, the mental illness or disease of the central nervous system that can be treated by administration of a therapeutic composition described herein is selected from depression, bipolar disorder, schizophrenia, anxiety, anxiety disorders, addiction, social phobia, major depressive disorder, treatment-resistant major depressive disorder (TR-MDD), major depressive disorder and its subtypes (melancholic depression, atypical depression, catatonic depression, postpartum depression, and seasonal affective disorder), Neurodegenerative amyloid disorders (Parkinson's, Alzheimer's, and Huntington's diseases) orthostatic tremor, Lafora disease, restless leg syndrome, neuropathic pain, pain disorders, dementia, epilepsy, stiff-person syndrome, premenstrual dysphoric disorder, autism spectrum disorder, sleep disorders, and attention deficit hyperactivity disorder (ADHD).

In some embodiments, the method further comprises decreasing at least one symptom of a mental disorder or disease of the central nervous system in the subject selected from the group consisting of fatigue, insomnia, motor dysfunction, stress, persistent anxiety, persistent sadness, social withdrawal, substance withdrawal, irritability, thoughts of suicide, thoughts of self-harm, restlessness, low sex drive, lack of focus, loss of appetite, seizures, memory loss, anger, bouts of emotional reactivity, confusion, pain, and muscle spasms.

Methods of Treatment

The therapeutic compositions described herein can be administered to a patient in need thereof, for instance for the treatment of a mental illness or disease of the central nervous system. In some embodiments, the method of treatment can comprise first diagnosing a patient who can benefit from treatment by a therapeutic composition described herein. In some embodiments, the method further comprises administering to the patient a therapeutic composition described herein.

Patient Diagnosis

In some embodiments, the process of identifying a subject with a mental illness or disease of the central nervous system can be carried out by a trained psychologist, psychiatrist, or neurologist. For instance, a psychiatrist, psychologist, or neurologist can diagnose a subject with a mental illness or disease of the central nervous system evaluating the subject's behavior for symptoms of the mental illness or disease of the central nervous system. One of skill in the art will understand that mental illness can also be identified in a subject with the aid of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), (American Psychiatric Association).

In one or more embodiments, the process of identifying a subject with a mental illness or disease of the central nervous system can comprise diagnosing the subject with a mental illness or disease of the central nervous system. In some embodiments, the mental illness or disease of the central nervous system is identified or diagnosed using fMRI. In some embodiments, mental illness or disease of the central nervous system can be identified with standard psychological and neurological surveys, or in other methods known to experts in the field.

In some embodiments, a subject in need of treatment with a therapeutic composition described herein can be identified by identifying low levels of GABA in the subject's blood, serum, stool, or other bodily fluid. In some embodiments, the amount of GABA in the subject's stool (e.g., the initial amount of GABA in the subject's stool) is below about 8 μg GABA per gram of stool. The amount of GABA can be measured using the wet or dry weight of stool by LC/MS or another technique known in the art. In some embodiments, the amount of GABA in the subject's blood or serum (e.g., the initial amount of GABA in the subject's blood or serum) is below about 10 μg/L+/−5 μg/L GABA per gram of blood or serum (e.g., as measured by LC/MS). In some embodiments, the amount of GABA in the prefrontal cortex, or other areas of the brain, is below about 1.0 mM/kg, as measured by proton magnetic resonance (PMR), or another similar technique.

In some embodiments, the percentage of GABA-producing bacteria in the subject's gut (e.g., the initial amount) represents about 10% of total 16S sequences as measured by sequencing using such methods as 16S rDNA gene Illumina sequencing or quantitative PCR. In some embodiments, the percentage of GABA-producing bacteria in the subject's gut represents about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1% of the total 16S sequences measured in the subject's gut.

Determination of the initial amount of GABA in a subject's blood, serum, regions of the brain, or stool can help identify subjects that can benefit from treatment by administration of GABA-producing bacteria. In some embodiments, a subject with an initial amount of GABA in the serum or blood below 10 μg/L GABA can benefit from administration of GABA-producing bacteria. In some embodiments, a subject with an initial amount of GABA in the serum or blood below 100 μg, below 50 μg, below 25 μg, below 20 μg, below 15 μg, below 10 μg, below 9 μg, below 8 μg, below 7 μg, below 6 μg, below 5 μg, below 4 μg, below 3 μg, below 2 μg, below 1 μg, below 0.5 μg, below 0.1 μg, below 0.01 μg, below 10 ng, or below 1 ng, or below 0.1 ng per L of blood or serum can benefit from administration of a GABA-producing bacteria.

In some embodiments, a subject with an initial amount of GABA in the brain, in regions such as the prefrontal cortex (or other areas of the brain), of about 1.0 mM/kg can benefit from treatment by administration of GABA-producing bacteria. In some embodiments, a subject with an initial amount of GABA in the brain, in such regions as the prefrontal cortex (or other areas of the brain), of below 100 mM, below 50 mM, below 25 mM, below 20 mM, below 15 mM, below 10 mM, below 9 mM, below 8 mM, below 7 mM, below 6 mM, below 5 mM, below 4 mM, below 3 mM, below 2 mM, below 1 mM, below 0.5 mM, below 0.1 mM, or below 0.01 mM, or below 0.001 mM GABA can benefit from treatment by administration of GABA-producing bacteria.

In some embodiments, a subject with an initial amount of GABA in stool below 8 μg GABA per gram of stool (wet or dry weight) can benefit from administration of GABA-producing bacteria. In some embodiments, a subject with an initial amount of GABA in the stool below 100 μg, below 50 μg, below 25 μg, below 20 μg, below 15 μg, below 10 μg, below 9 μg, below 8 μg, below 7 μg, below 6 μg, below 5 μg, below 4 μg, below 3 μg, below 2 μg, below 1 μg, below 0.5 μg, below 0.1 μg, below 0.01 μg, below 10 ng, or below 1 ng, or below 0.1 ng per gram of stool can benefit from administration of a GABA-producing bacteria.

In some embodiments of any of the above aspects, the amount of GABA is increased 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000, or more percent in the subject's stool relative to the initial amount of GABA in the subject's stool, e.g., as measured in step (b) of any of the above-aspects. In some embodiments, the amount of GABA is increased 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000, or more percent in the subject's blood or serum relative to the initial amount of GABA in the subject's blood or serum, e.g., as measured in step (b) of any of the above-aspects. In some embodiments, the amount of GABA is increased 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000, or more percent in regions of the subject's brain, such as, but not limited to the prefrontal cortex, relative to the initial amount of GABA in the subject's brain, e.g., as measured in step (b) of any of the above-aspects. In some embodiments, at least one GABA-producing bacteria is increased 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000, or more percent in the subject's stool relative to the initial amount of GABA-producing bacteria in the subject's stool, e.g., as measured in step (b) in any of the above-aspects. In some embodiments, the level of expression of at least one GABA producing enzyme is increased 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000, or more percent in the subject's stool relative to the initial level of expression of GABA-producing enzymes in the subject's stool, as measured by qPCR or some other appropriate method, known to those familiar in the field.

In some embodiments of the disclosure, the amount of GABA-consuming bacteria can be reduced, e.g., reduced in the subject's stool, blood serum, and the like. The GABA-consuming bacteria can be, for instance, Evtepia gabavorous or Firmicutes bacterium MGS:114. In some embodiments, GABA-consuming bacteria can be reduced by 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, 3000, 4000, 5000, or more percent.

Accordingly, the present disclosure provides for the treatment of mental illness or disease of the central nervous system comprising administering to the subject GABA-producing bacteria, or prebiotics to stimulate growth or GABA production capabilities of GABA producing bacteria.

Methods of Culturing GABA-Consuming Bacteria

In some embodiments, the present disclosure provides a method of culturing bacteria that require GABA for survival and replication. In some cases, these bacteria were previously uncultured or unculturable. In some cases, the bacteria are cultured by supplying endogenous GABA to the growth medium. In some embodiments, the bacteria are cultured by co-culturing the bacteria with a different bacterium capable of producing GABA (e.g., a bacterium as described above).

In some embodiments, the previously uncultured bacterium is E. gabavorous. E. gabavorous can be cultured on a suitable substrate such as agar. In some embodiments, the agar can contain added GABA. In some embodiments, the present disclosure provides a method of culturing E. gabavorous comprising co-culturing E. gabavorous with another bacterial strain, said strain is capable of producing GABA, for instance at conditions that are physiologically relevant and found in to the human gastrointestinal tract (e.g., pH less between about 4.5 and about 7.5).

Without wishing to be bound by theory, some previously unculturable bacteria (e.g., E. gabavorous) may be able to grow in proximity to cultivable organisms producing growth factors necessary for bacteria to survive or grow. Accordingly, the present disclosure teaches the discovery and culture of E. gabavorous in the presence of GABA as a necessary growth factor.

E. gabavorous was identified as a late-growing colony in spatial proximity to Bacteroides fragilis KLE1758. It was found that growth of E. gabavorous KLE1738 was induced in the presence of supernatant derived from Bacteroides fragilis KLE1758. Chemical analysis via HPLC and NMR of Bacteroides fragilis KLE1738 supernatant revealed GABA as the necessary growth factor for E. gabavorous.

As set forth in FIGS. 1A-B, and Example 2, E. gabavorous was initially found because it grew in the presence of Bacteroides fragilis KLE1758. It was proposed that Bacteroides fragilis KLE1758 produces a growth factor that is necessary for the growth and survival of E. gabavorous. FIG. 1A shows a photograph of an agar plate containing colonies of bacteria after treatment with human stool. The inset at the top right shows a close-up of a colony of KLE1758 along with a colony of 1738 that is growing in the immediate proximity. FIG. 1B shows a colony of KLE1758 that is capable of supporting multiple colonies of KLE1738 on an agar plate with no other bacteria. Without wishing to be bound by theory, Bacteroides fragilis KLE1758 can support the growth of E. gabavorous KLE1738. Without wishing to be bound by theory, Bacteroides fragilis KLE1758 and E. gabavorous KLE1738 can co-exist in a symbiotic relationship in which E. gabavorous KLE1738 can consume the GABA that is produced by Bacteroides fragilis KLE1758.

As shown in FIGS. 2A-G and Examples 3-4, the supernatant from a 48-hour culture of Bacteroides fragilis KLE1758 was found to support the growth of E. gabavorous KLE1738, whereas standard agar was not. After a series of purification and isolation steps of the KLE1758 supernatant, it was discovered that GABA was responsible for the growth of E. gabavorous KLE1738. FIG. 2A shows that E. gabavorous KLE1738 grew in the presence of supernatant of Bacteroides fragilis. However, FIG. 2B shows that E. gabavorous KLE1738 did not grow in the presence of sterile vehicle on standard agar. After a first fractionation of the Bacteroides fragilis KLE1758 spent medium, it was found that the most polar fragment was capable of inducing the growth of E. gabavorous KLE1738 (FIG. 2C), but that less polar fragments could not induce growth (FIG. 2D). FIGS. 2E and 2F show close-up views demonstrating that the most polar fraction of the Bacteroides fragilis KLE1758 supernatant could induce growth of E. gabavorous KLE1738 (FIG. 2E), whereas less polar fragments could not (FIG. 2F). As shown in FIG. 2G, only GABA was identified as being capable of inducing growth of E. gabavorous KLE1738.

The 16S nucleotide sequence of E. gabavorous KLE1738 is given in Seq. ID No. 2286.

The genetic sequence of E. gabavorous KLE1738 was identified as set forth in Example 5. The annotated genome (2,500,009 bp) of E. gabavorous is given in the attached Sequence Listing comprising SEQ. ID Nos. 1-2288 and is given in SEQ ID Nos. 2218-2285. Without wishing to be bound by theory, the genome revealed no obvious entry points for metabolism of common sugars or other carbon sources.

Without wishing to be bound by theory, it was discovered that transport systems for common sugars or other carbon sources were also incomplete. Without wishing to be bound by theory, their absence suggests a recent loss of function. E. gabavorous is predicted to have a limited set of transporters, including those for methionine, branched-chain amino acids, dipeptides, oligopeptides, and choline/betaine, as predicted in Table 10.

TABLE 10 Predicted Transport Systems in E. gabavorous. Category Subsystem Role Amino Acids and Derivatives Polyamine Metabolism ABC transporter, periplasmic spermidine putrescine-binding protein PotD (TC 3.A.1.11.1) Amino Acids and Derivatives Polyamine Metabolism Spermidine Putrescine ABC transporter permease component PotB (TC 3.A.1.11.1) Amino Acids and Derivatives Polyamine Metabolism Spermidine Putrescine ABC transporter permease component PotC (TC 3.A.1.11.1) Amino Acids and Derivatives Methionine Biosynthesis Methionine ABC transporter ATP-binding protein Amino Acids and Derivatives Methionine Biosynthesis Methionine ABC transporter permease protein Amino Acids and Derivatives Methionine Biosynthesis Methionine ABC transporter substrate-binding protein Amino Acids and Derivatives Methionine Degradation Methionine ABC transporter ATP-binding protein Amino Acids and Derivatives Methionine Degradation Methionine ABC transporter permease protein Amino Acids and Derivatives Methionine Degradation Methionine ABC transporter substrate-binding protein Clustering-based PhoR-PhoB two-component Phosphate ABC transporter, periplasmic subsystems regulatory system phosphate-binding protein PstS (TC 3.A.1.7.1) Membrane Transport ABC transporter dipeptide (TC Dipeptide-binding ABC transporter, periplasmic 3.A.1.5.2) substrate-binding component (TC 3.A.1.5.2) Membrane Transport ABC transporter oligopeptide (TC Oligopeptide ABC transporter, periplasmic 3.A.1.5.1) oligopeptide-binding protein OppA (TC 3.A.1.5.1) Membrane Transport ABC transporter branched-chain Branched-chain amino acid ABC transporter, amino acid (TC 3.A.1.4.1) amino acid-binding protein (TC 3.A.1.4.1) Phosphorus Metabolism High affinity phosphate transporter Phosphate ABC transporter, periplasmic and control of PHO regulon phosphate-binding protein PstS (TC 3.A.1.7.1) Phosphorus Metabolism Phosphorus Metabolism Phosphate ABC transporter, periplasmic phosphate-binding protein PstS (TC 3.A.1.7.1) Stress Response Choline and Betaine Uptake and L-proline glycine betaine ABC transport system Betaine Biosynthesis permease protein ProV (TC 3.A.1.12.1) Stress Response Choline and Betaine Uptake and Glycine betaine ABC transport system, glycine- Betaine Biosynthesis betaine-binding protein OpuAC Stress Response Choline and Betaine Uptake and Glycine betaine ABC transport system, permease Betaine Biosynthesis protein OpuAB Stress Response Choline and Betaine Uptake and L-proline glycine betaine binding ABC transporter Betaine Biosynthesis protein ProX (TC 3.A.1.12.1) Sulfur Metabolism Alkanesulfonate assimilation ABC-type nitrate/sulfonate/bicarbonate transport system, ATPase component Sulfur Metabolism Alkanesulfonate assimilation Alkanesulfonates ABC transporter ATP-binding protein

Without wishing to be bound by theory, these amino acids are not usually capable of supporting bacterial growth as single carbon sources, unlike serine, threonine, glutamate, and others. This is supported by the inability of E. gabavorous to grow on the tested amino acids.

Without wishing to be bound by theory, the metabolic pathway of E. gabavorous is proposed to be similar to that of Clostridium aminobutyricum, as set forth in FIG. 3, as all enzymes in this pathway were identified in the E. gabavorous genome (Table 11).

TABLE 11 Enzymes in E. gabavorous GABA fermentation pathway, predicted by RAST Enzyme # Contig Start Stop Length (bp) Function 1 KLE1738_5 26729 28084 1356 Gamma-aminobutyrate:alpha-ketoglutarate aminotransferase (EC 2.6.1.19) 2 KLE1738_5 25576 26688 1113 NAD-dependent 4-hydroxybutyrate dehydrogenase (EC 1.1.1.61) 3 KLE1738_2 195690 197033 1344 4-hydroxybutyrate:acetyl-CoA CoA transferase (EC 2.8.1.—) 3 KLE1738_28 9343 10665 1323 4-hydroxybutyrate:acetyl-CoA CoA transferase (EC 2.8.1.—) 3 KLE1738_5 24249 25547 1299 4-hydroxybutyrate:acetyl-CoA CoA transferase (EC 2.8.1.—) 3 KLE1738_7 87690 86401 1290 4-hydroxybutyrate:acetyl-CoA CoA transferase (EC 2.8.1.—) 4 KLE1738_5 22352 23902 1551 4-hydroxybutanoyl-CoA dehydratase (EC 4.2.1.—)/Vinylacetyl-CoA Delta- isomerase (EC 5.3.3.3) 5 KLE1738_6 2958 2092 867 Enoyl-CoA hydratase (EC 4.2.1.17) 5 KLE1738_11 1132 356 777 Enoyl-CoA hydratase (EC 4.2.1.17) 6 KLE1738_6 4710 5762 1053 3-hydroxybutyryl-CoA dehydrogenase (EC 1.1.1.35) 6 KLE1738_8 87921 88769 849 3-hydroxybutyryl-CoA dehydrogenase (EC 1.1.1.35) 7 KLE1738_14 4910 6139 1230 Acetyl-CoA acetyltransferase (EC 2.3.1.9) 7 KLE1738_19 28638 27382 1257 Acetyl-CoA acetyltransferase (EC 2.3.1.9) 8 KLE1738_13 26709 25738 972 Phosphate acetyltransferase (EC 2.3.1.8) 9 KLE1738_1 119924 121141 1218 Acetate kinase (EC 2.7.2.1) 1b KLE1738_30 8650 9999 1350 NADP-specific glutamate dehydrogenase (EC 1.4.1.4) 5b KLE1738_6 4303 3083 1221 Butyryl-CoA dehydrogenase (EC 1.3.8.1) 6b KLE1738_1 158124 159767 1644 Acetyl-CoA:acetoacetyl-CoA transferase (EC 2.8.3.8)

The pH dependency of B. fragilis KLE1758's ability to produce GABA was investigated. As set forth in Example 6, B. fragilis KLE1758 was grown at various pH values, and the supernatant from that growth was analyzed using LCMS. As shown in FIG. 4A, GABA is produced primarily at relatively lower pH (e.g., about 5.5 and below), compared with glutamate.

Accordingly, it was found that B. fragilis KLE1758 can produce GABA at low pH, whereas it was found to produce primarily glutamate at relatively high pH. As set forth in Example 6 and FIG. 4A, at a pH of about 5 and about 5.5, B. fragilis KLE1758 produced considerably more GABA than glutamate. However, at a pH of about 6 and about 6.5, B. fragilis KLE1758 was found to produce primarily glutamate and relatively low quantities of GABA.

Biological Screens for GABA-Producers

The present disclosure also teaches methods of identifying bacteria that can produce GABA. Given the strict requirement of GABA for the growth of E. gabavorous, the present disclosure provides methods of screening for bacteria capable of producing GABA using, for instance, E. gabavorous and/or other GABA-dependent bacterial growth as a bioassay. Importantly, by using buffered media (e.g., buffered agar), the assay technique set forth herein can be used to identify bacteria that are capable of producing bacteri at various pH values (e.g., between about 5.5 to about 7.5).

As set forth in Example 7, a sample that is thought to contain GABA-producing bacteria, such as a human stool sample, can be mixed with molten agar. The agar, containing the bacterial sample, can then be streaked with a dilute solution of E. gabavorous. As shown herein, E. gabavorous cannot grow in the absence of GABA, and therefore any colonies of E. gabavorous that do form will necessarily grow in close spatial proximity to GABA-producers.

Because GABA production by some bacteria, including E. coli, only occurs at a very low pH (e.g., at a pH not relevant to the human gut), the assay method set forth herein was adapted to control the pH of the media, enabling identification of organisms capable of producing GABA at a pH between about 4.5 and about 7.5. Without wishing to be bound by theory, the pH of between about 4.5 and about 7.5 is the relevant pH within the human gut. Accordingly, bacteria that can produce GABA at these pH values can in some embodiments be capable of producing GABA in the human gut.

In other words, by controlling the pH of the growth medium (e.g., by buffering the molten agar), the present disclosure can allow one to distinguish between GABA-producers that are capable of producing GABA at a physiologically relevant pH (e.g., between about 4.5 to about 7.5) from bacteria that are not able to produce GABA at a physiological relevant pH (e.g., bacteria that can only produce substantial quantities of GABA below pH of about 4.5).

Using this method, a number of representatives from multiple genera, including, but not limited to, Bacteroides, Bifidobacterium, Blautia, Coprococcus, Gordonibacter, Dorea, and Clostridium were identified. FIG. 4B shows a representative agar plate showing growth of E. gabavorous in the presence of a GABA-producing bacteria. FIG. 4C shows a phylogenetic tree of GABA-producing bacteria that were identified using this method.

FIG. 5 shows the GABA production capabilities of certain strains of GABA producers identified using the techniques described herein. As set forth in FIG. 5, eight strains of GABA producers were grown in buffered media (e.g., between about pH 4.5 and about pH 5.0; and between about pH 6.5 and about pH 7.0). Using the method described in Example 6, the GABA-producing capabilities of the GABA-producing bacteria at various pH values were investigated. As set forth in FIG. 5, certain bacteria (e.g., B. dorei KLE1912) produced relatively similar quanties of GABA at lower pH (e.g., between about 4.5 and about 5.0). In contrast, certain bacteria produced different amounts of GABA depending on the pH (e.g., B. vulgatus KLE1910 and B. ovatus KLE1770). Notably, as shown for B. vulgatus KLE1910 and B. ovatus KLE1770, some bacteria were found to produce relatively more GABA at lower pH than at higher pH, whereas some bacteria were found to produce relatively more GABA at higher pH than at lower pH.

In some embodiments of the method of identifying bacteria capable of producing GABA, the substrate is agar. In some embodiments, the step of contacting the substrate with E. gabavorous comprises streaking the agar with a dilute solution of E. gabavorous. The GABA-producing colonies are then identified by growth induction of E. gabavorous. As set forth above, growth E. gabavorous is used to determine if a bacterial strain produces GABA. However, one of skill in the art will understand that any bacteria that has a strict requirement of GABA for growth and survival can likewise be used as described above to identify bacteria that can produce GABA.

EXAMPLES

The disclosure is further illustrated by the following examples and synthesis examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly.

Unless otherwise specified, PCR was performed using the general bacterial primers 27F (5′-AGAGTTTGATCMTGGCTCAG-3′) (set forth in Seq ID No. 2287) and 1492R (5′-TACGGYTACCTTGTTACGACTT-3′) (set forth in Seq ID No. 2288) to amplify the 16S rRNA gene. The PCR reaction mixture was 12.5 μL GoTaq Master Mix (Promega), 1 μL 10 μM 27F and 1492R primers, 9.5 μL Nuclease Free Water (Promega), and 1 μL of a colony resuspended in 100 μL sterilized distilled water. The amplification conditions were one cycle of 95° C. for 5 min; 30 cycles of 95° C. for 30 s, 55° C. for 30 s; 72° C. for 90 s; and finally one cycle of 72° C. for 7 min. Amplification of PCR reactions were then confirmed using gel electrophoresis on a 0.8% agarose gel loaded saturated with ethidium bromide. Successful PCRs were sequenced by Macrogen Corporation using the 27F primer using the Applied Biosystems 3730xl DNA analyzer. Quality control for sequences was performed using DNA Baser (www.DnaBaser.com), in which ends were trimmed until there were more than 75% good bases (defined by having a QV score of higher than 25) in an 18 base window. Identification of phylogenetic neighbors and calculation of pairwise sequence similarity were carried out using the EzTaxon server.

Example 1: Human Stool Collection

Stool samples from a healthy human donor were collected using a commercially available stool collection vessel. Within 5 minutes of collection, 1 gram of stool was resuspended in 9 mL of sterile 20% glycerol in PBS and homogenized for 30 seconds using a vortex. 1 mL aliquots of this mixture were loaded in cryotubes and stored at −80° C. for cultivation.

Example 2: Cultivation of Helper-Uncultured Pairs from Human Stool Samples

All cultivation work was performed in a Coy Anaerobic Vinyl chamber with an atmosphere of 5% hydrogen, 10% CO₂, 85% nitrogen. Anaerobically, serial dilutions of thawed stool samples were prepared in PBS and bead spread (7-10 beads/plate) on 1× Fastidious Anaerobic Agar (Accumedia) plates with 2.5% yeast extract (FAAy). Plates were incubated at 37° C. anaerobically for one week, and each day appearance of colonies were tracked by spotting the outside of the plates with different colored markers. At the end of the week, serial dilutions of late forming colonies (appearance after 4-7 days) were prepared in PBS and bead spread on FAAy plates. Nearby (<2 cm), early forming colonies (appearance after 1-3 days) were then resuspended in PBS at a high density. Five μL of this suspension were spotted on the plates with their respective spread-candidate dependent and incubated for up to one week in the chamber, and observed daily. Growth induction of the dependent organism around the spotted helper indicated a positive hit.

A fecal sample from a healthy human donor was diluted and spread-plated on rich medium, and newly formed colonies were noted daily for a week. Late forming colonies (3-7 days) were diluted and spread on a nutrient agar plate, and a heavy inoculum of a neighboring, early forming colony (1-2 days) was spotted, as shown in FIG. 1A. Using this method, a number of helper-uncultured pairs were identified, in which the spread-plated uncultured isolate formed a gradient of growth around the spotted culturable helper.

One isolate, E. gabavorous KLE1738 (93.22% similar to Flavonifractor plautii ATCC 29863 by 16S rRNA gene sequence), was dependent on Bacteroides fragilis KLE1758 (100% similar to Bacteroides fragilis ATCC 25852 by 16S rRNA gene sequence) for growth (FIG. 1B). E. gabavorous, is a gram positive organism of the Clostridia class.

Example 3: Determination of GABA as Growth Factor for E. gabavorous

The supernatant of a 48-hour culture of B. fragilis KLE1758 grown in rich medium induced growth of E. gabavorous as shown in FIGS. 2A and 2B, enabling bioassay-driven purification of the growth factor. The supernatant was solvent-partitioned with ethyl acetate, and the water residue fraction induced the growth of E. gabavorous. The water fraction was then purified using HP-20 column chromatography, and the most polar fraction induced the growth of E. gabavorous as shown in FIG. 2C. This active fraction was then further fractionated by preparative HPLC. HPLC yielded one active fraction, and NMR showed that it contained 10 compounds, primarily GABA, threonine, lactic acid, valine, glutamine, malonic acid, succinic acid, and alanine. All compounds were spotted on plates where E. gabavorous was spread, and only GABA caused growth induction, as shown in FIGS. 2E-F. The compounds were identified by NMR analysis including ¹H, ¹³C, ¹H-¹H COSY, TOCY, HSQC, and HMBC NMR experiments to identify the constituents in the fraction. All NMR experiments were carried out on a Varian INOVA 600 MHz NMR spectrometer equipped with an indirect detection probe.

Example 4: Testing Other Compounds for Induction of E. gabavorous

Multiple compounds were tested for the ability to induce the growth of E. gabavorous as shown in FIG. 2G. Stocks of each compound (purchased from Sigma, excluding the ATCC Mineral and Vitamin mixes) were prepared dependent on solubility in water at the concentrations shown in FIG. 2G. Five μL of the stocks were then spotted on FAAy plates spread with E. gabavorous, and incubated anaerobically for one week, and any growth was observed. No compounds induced growth but GABA.

Example 5: Whole Genome Sequencing and Annotation

DNA from cells of E. gabavorous grown 48 hours anaerobically on FAAy plates with 1.0 mg/mL GABA was isolated for genome sequencing using the PowerSoil® DNA Isolation Kit (Mo Bio, San Diego, Calif.) to manufacturer specifications, yielding ˜5.0 μg of high quality DNA. Genomic sequencing and de novo assembly was performed by the Genomic Core at Tufts University in Boston, Mass. The genome of E. gabavorous was sequenced on an Illumina MiSeq using MiSeq V2 500 cycles chemistry with a paired-end 250 bases format. Briefly, 100 ng of genomic DNA was sheared on a Covaris M220 to an average fragment size of around 600 bases. Using the fragmented DNA as input, a sequencing library was prepared with Illumina TruSeq Nano DNA Sample Preparation Kit per the manufacturer instruction. Base calling and demultiplexing was performed on the raw data from the MiSeq using CASAVA and fastq files were generated. De novo assembly of the genome was performed using Edena V3.131028 with a customized parameter optimization pipeline. The best assembled genome, as assessed by the contig statistic, was reported. Assembly yielded 68 contigs (n), with all contigs having a sequence length longer than 200 bases (n:200). 7 contigs with a larger value than the N50 (119748), and the minimal contig length is 355 (min). The N20, N50 and N20 are 33403, 119748 and 204670, respectively. The largest contig length (max) was 344080, and the estimated genome size is 2500009. The draft genome was annotated using the RAST server and the KAAS (KEGG Automatic Annotation Server) analysis tool of the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. The genome of E. gabavorous was annotated using RAST, and the genomes of CAG:113 and E. gabavorous were compared using RAST.

Example 6: Quantification of Glutamate and GABA Production in B. fragilis

The absolute amount of glutamate and GABA contained in the B. fragilis KLE1758 supernatant was determined by HPLC, using a fluorophore to aid in detection. Specifically, free amines were labeled for analysis by reacting with the AccQ reagent (Waters) according to manufacturer's protocols. A calibration curve was generated from stock solutions (10 mg/mL) that were prepared by dissolving GABA (2.0 mg) in water (200 μL), glutamate (Glu) (10.2 mg) in water (1020 μL) and cysteic acid (CSA) (16.9 mg) in water (1690 μL). These were serially diluted to generate a concentration gradient. Specifically, stocks were made to final concentrations of 0.1 mg/mL, 0.05 mg/mL, 0.01 mg/mL and 0.001 mg/mL. An aliquot of a given stock solution, was added to the AccQ reaction buffer (25 μL final), followed by the addition of the acetonitrile-dissolved AccQ reagent (25 μL). This was reacted for ten minutes at 55-60° C., and then transferred directly to an LCMS vial, fitted with a glass insert. Reaction concentrations of the amino acids were: 20 ng/μL, 10 ng/μL, 5 ng/μL, 2.5 ng/μL, 1 ng/μL, 0.5 ng/μL, 1 ng/μL and 0 ng/μL (control). These samples were injected (10 μL) on an Agilent LCMS, using a gradient of solvent A (water/0.1% formic acid) and B (acetonitrile/0.1% formic acid) over the following time course: 1) 0-40 minutes linear gradient of 2% B to 98% B; 2) 40-45 min isocratic at 98% B; 3) 45-45.5 min linear gradient of 98% B to 2% B; 4) 45.5-55 min isocratic at 2% B. The CSA-AccA derivative eluted at 9.5 min, the Glu-AccQ derivative eluted at 12.1 min and the GABA-AccQ derivative at 12.5 min. The area under the curve, in extracted ion (EIC) mode (m/z=274 for GABA-AccQ, 318 for Glu-AccQ and 340 for CSA-AccQ), was used to develop a calibration curve by plotting area against amount of original Glu, CSA or GABA (in ng) injected. An average of two runs for each tested concentration was used to generate the calibration curve. In the case of GABA and Glu, CSA was added to all reactions, to a final concentration of 2.5 μg/mL, and used as an internal standard.

Triplicate cultures of B. fragilis KLE1758 were grown in BHIych anaerobically for 48 hours, the cells centrifuged, and the supernatant was filtered through a 0.2 μm filter. Samples were stored at 4° C. until analysis. To analyze the samples, an aliquot (2 μL) of each sample was added to AccQ reaction buffer (16 μL), CSA internal standard (2 μL of a 50 μg/mL solution in buffer), followed by the addition of the AccQ reagent (20 μL). These samples were heated to 55° C. for ten minutes, and then transferred directly into an LCMS vial fitted with a glass insert. An aliquot of each sample (10 μL) was injected onto the LCMS, and separated following the same injection program as used for the calibration curve. The total EIC area under curves representing GABA, Glu and CSA was determined using ChemStation software (Agilent). Each injection represented 25% of the original media concentration, therefore the total amount of sample determined (in ng) was multiplied by a factor of four to determine the original concentration (in ng/μL=μg/mL). All areas were normalized to the area under the curve of the internal standard (CSA), which was held at constant concentration throughout the experiment. The results are given in FIG. 4A.

Example 7: Co-Culture Screen for GABA Producers Using E. gabavorous

GABA secretion can allow bacteria to survive acid stress. Decarboxylation of glutamate produces GABA, which is exported from the cell in a protonated form, alkalinizing the cytoplasm. E. coli, as well as some Lactobacillus and Bifidobacterium strains were shown to produce GABA, but these organisms are typically found at a low abundance in the human intestinal tract, and in the case of E. coli, is dependent on low pH (e.g., about 4.2 and below). Bacteroides fragilis, the helper of E. gabavorous, is a common gut bacterium, but it was found that similarly to E. coli, GABA production by Bacteroides fragilis KLE1758 is only observed at a pH less than about 5.5 as shown in FIG. 4A. GABA is shown in left-hand columns and glutamate is shown in right-hand columns at each pH value. Without wishing to be bound by theory, it was therefore considered useful to identify microorganisms capable of producing GABA at a physiologically relevant pH for the human large intestine (e.g., pH of about 5.5 to about 7.5, or about pH 5.7 to about 7.4).

To accomplish this, the strict GABA requirement of E. gabavorous was utilized to screen for bacteria capable of secreting GABA on heavily buffered medium. Metabolic byproducts of bacterial growth may lower the pH of the medium in the absence of buffer. Stool sample was mixed with molten agar and poured in Petri plates in an anaerobic chamber, and E. gabavorous was spread on top of the agar once solidified. By looking for zones of growth induction of E. gabavorous, and measuring the pH of the agar, bacteria that produce GABA at a pH of between about 6.0 and about 7.0 were identified, as well as those producing GABA at a pH of about 4.5 to about 5.0, as shown in FIG. 4B. The full 16S rRNA gene was amplified and sequenced using the 27F and 1492R universal primers, and annotation with EZTaxon revealed a number of representatives from multiple genera, including Bacteroides, Bifidobacterium, Blautia, Coprococcus, Gordonibacter, Dorea, and Clostridium (FIG. 4C). Of these, only Bifidobacterium adolescentis was previously reported to produce GABA.

Example 8: Using an Engineered Escherichia coli Strain to Produce GABA and Induce the Growth of E. gabavorous

GABA can be produced by intestinal epithelial cells and by some bacteria, such as Escherichia coli and Listeria monocytogenes, by decarboxylation of glutamate. In E. coli, the decarboxylation of glutamate serves as a mechanism to decrease intracellular pH, and GABA production generally occurs at a low pH. To survey whether E. coli could be engineered to produce GABA, E. coli colones harboring native glutamate decarboxylases (gadA, gadB), or the GABA antiporter, (gadC) in the pCA24N IPTG inducible high-copy number vector, were tested for GABA production via co-cultivation assay with E. gabavorous. Overexpression of glutamate decarboxylase in E. coli (gadA or gadB), resulted in induction of KLE1738 growth to levels seen with B. fragilis, while expression of the GABA antiporter, gadC, did not (FIG. 6). Altering the pH of growth media for KLE1738 did not change the GABA-dependency phenotype. Without wishing to be bound by theory, this suggests that engineering bacteria to overexpress glutamate decarboxylase or other GABA producing enzymes, constitutively or inducibly, is an effective way to produce GABA, as well as induce the growth of E. gabavorous.

EQUIVALENTS

While the present disclosure has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present disclosure. 

1. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutic composition comprising at least one purified bacterial population that produces GABA at a pH range of between 4.5 and 7.5, the at least one purified bacterial population consisting of bacteria comprising a 16s rDNA sequence at least 98% identical to a 16s rDNA sequence selected from the group consisting of SEQ ID NOs: 1-4, 8, 10, 12, 16-18, 28-29 and
 81. 2. The method of claim 1, wherein the at least one bacterial population consists of bacteria comprising a 16S rDNA sequence at least 99% identical to a 16S rDNA sequence selected from the group consisting of SEQ ID NOs: 1-4, 8, 10, 12, 16-18, 28-29 and
 81. 3. The method of claim 1, wherein the disease or disorder is a mental disease or disorder.
 4. The method of claim 3, wherein the mental disease or disorder is selected from the group consisting of depression, bipolar disorder, schizophrenia, anxiety, anxiety disorders, addiction, social phobia, treatment-resistant major depressive disorder (TR-MDD), major depressive disorder and its subtypes, neurodegenerative amyloid disorders, orthostatic tremor, Lafora disease, restless leg syndrome, neuropathic pain, pain disorders, dementia, epilepsy, stiff-person syndrome, premenstrual dysphoric disorder, autism spectrum disorder, sleep disorders, and attention deficit hyperactivity disorder (ADHD), and combinations thereof.
 5. The method of claim 4, wherein: (a) the subtype of major depressive disorder comprises melancholic depression, atypical depression, catatonic depression, postpartum depression, or seasonal affective disorder; and (b) the neurodegenerative amyloid disorder comprises Parkinson's disease, Alzheimer's disease, or Huntington's disease.
 6. The method of claim 1, wherein treating a disease or disorder comprises decreasing at least one symptom of the disease or disorder.
 7. The method of claim 6, wherein the at least one symptom comprises fatigue, insomnia, motor dysfunction, stress, persistent anxiety, persistent sadness, social withdrawal, substance withdrawal, irritability, thoughts of suicide, thoughts of self-harm, restlessness, low sex drive, lack of focus, seizures, memory loss, anger, bouts of emotional reactivity, confusion, pain, muscle spasms, loss of appetite, altered intestine motility, or a combination thereof.
 8. The method of claim 1, wherein the at least one purified bacterial population consists of bacteria selected from the group consisting of: Bacteroides caccae; Bacteroides clarus; Bacteroides dorei; Bacteroides finegoldii; Bacteroides stercoris; Bacteroides uniformis; Bacteroides xylanisolvens; Butyricimonas virosa; Clostridium perfringens; Clostridium sordellii; Parabacteroides distasonis; Parabacteroides merdae; Ruminococcus gnavus; Bacteroides salyersiae, and combinations thereof.
 9. The method of claim 1, wherein the at least one purified bacterial population consists of bacteria comprising a DNA sequence which encodes an enzyme selected from: glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof.
 10. The method of claim 9, wherein the glutamate decarboxylase; putrescine aminotransferase; gamma-aminobutyraldehyde dehydrogenase; arginine decarboxylase; agmatinase; ornithine decarboxylase; or a combination thereof, is encoded by a DNA sequence at least 50% identical in DNA sequence to any one of Seq. ID. NOs: 275-304.
 11. The method of claim 9, wherein: (a) the glutamate decarboxylase is encoded by a DNA sequence at least 50% identical in DNA sequence to a sequence selected from SEQ ID NOs: 275-279; (b) the putrescine aminotransferase is encoded by a DNA sequence at least 50% identical to a sequence selected from the group consisting of SEQ ID NOs: 280-284; (c) the gamma-aminobutyraldehyde dehydrogenase is encoded by a DNA sequence at least 50% identical to a sequence selected from the group consisting of SEQ ID NOs: 285-289; (d) the arginine decarboxylase is encoded by a DNA sequence at least 50% identical to a sequence selected from the group consisting of SEQ ID NOs: 290-294; (e) the agmatinase is encoded by a DNA sequence at least 50% identical to a sequence selected from the group consisting of SEQ ID NOs: 295-299; or (f) the ornithine decarboxylase is encoded by a DNA sequence at least 50% identical to a sequence selected from the group consisting of SEQ ID NOs: 300-304.
 12. The method of claim 1, wherein the composition is in the form of a capsule, a tablet, a caplet, a pill, a troche, a lozenge, a powders, a granule, a medical food, a fecal transplant or a combination thereof.
 13. The method of claim 1, wherein the composition comprises a prebiotic.
 14. The method of claim 1, wherein the composition is administered as a fecal transplant.
 15. The method of claim 1, wherein the composition is administered as a probiotic.
 16. The method of claim 1, further comprising identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of GABA in the subject's stool, blood, serum or brain.
 17. The method of claim 16, wherein: (a) the initial amount of GABA in the subject's stool is below about 8 μg per gram of wet or dry stool; (b) the initial amount of GABA in the subject's blood or serum is below about 10 μg per liter of blood; or (c) the initial amount of GABA in the subject's brain is below about 1.0 mM/kg.
 18. The method of claim 16, wherein an initial amount of GABA-producing bacteria in the subject's stool is less than about 10% of total bacteria as measured by 16S sequence mapping.
 19. The method of claim 16, wherein the amount of GABA in the subject's stool, blood, serum or brain is increased relative to the initial amount after administering the therapeutic composition.
 20. The method of claim 1, further comprising identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of expression of GABA-producing enzymes in the subject's stool.
 21. The method of claim 20, wherein the GABA-producing enzymes are selected from glutamate decarboxylase, putrescine aminotransferase, gamma-aminobutyraldehyde dehydrogenase, arginine decarboxylase, agmatinase, ornithine decarboxylase, and combinations thereof.
 22. The method of claim 20, wherein the expression of enzymes is increased relative to the initial amount of enzyme expression after administering the therapeutic composition.
 23. The method of claim 1, further comprising identifying a subject in need of treatment by determining whether the subject would benefit from an increase in endogenous GABA by measuring an initial amount of GABAergic response in the subject's brain. 